Stem Cell Treatment Autism - ASCI - Asian Stem Cell Institute

Stem Cell Treatment Autism - ASCI - Asian Stem Cell Institute
http://www.stem-cell-regeneration.com/autism-stem-cell-treatm...
Stem Cell Treatments for Autism are currently available at ASCI
Autism Background: About a third to a half of individuals with autism do not develop enough natural speech to meet their daily
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communication needs. Differences in communication may be present from the rst year of life, and may include delayed onset of babbling, unusual gestures, diminished responsiveness, and vocal patterns that are not synchronized with the caregiver. In the second and third years, autistic children have less frequent and less diverse babbling, consonants, words, and word combinations; their gestures are less often integrated with words. Autistic children are less likely to make requests or share experiences, and are more likely to simply repeat others' words (echolalia) or reverse pronouns. Joint attention seems to be necessary for functional speech, and decits in joint attention seem to distinguish infants with ASD. for example, they may look at a pointing hand instead of the pointed-at object, and they consistently fail to point at objects in order to comment on or share an experience. Autistic children may have difculty with imaginative play and with developing symbols into language.
Repetitive behavior
Forms of repetitive or restricted behavior (RBS-R):
Stereotypy is repetitive movement, such as hand flapping, making sounds, head rolling, or body rocking. Compulsive behavior is intended and appears to follow rules, such as arranging objects in stacks or lines. Sameness is resistance to change; for example, insisting that the furniture not be moved or refusing to be interrupted. Ritualistic behavior involves an unvarying pattern of daily activities, such as an unchanging menu or a dressing ritual. This is closely associated with sameness and an independent validation has suggested combining the two factors. Restricted behavior is limited in focus, interest, or activity, such as preoccupation with a single television program, toy, or game. Self-injury includes movements that injure or can injure the person, such as eye poking, skin picking, hand biting, and head banging. A 2007 study reported that self-injury at some point affected about 30% of children with ASD.
No single repetitive or self-injurious behavior seems to be specic to autism, but only autism appears to have an elevated pattern of occurrence and severity of these behaviors.
Autism Case Study - STEM CELL AUTISM TREATMENT
Autism treatment studies and stem cell protocols:

[Value of the experiment for developmental neurology]. Related Articles [Value of the experiment for developmental neurology]. Przegl Lek. 2009;66(11):958-62 Authors: Budziszewska B, Laso W, Steczkowska M, Gergont A Abstract Some neurological diseases cannot be at present efficiently treated, because of their unknown pathogenesis and the lack of appropriate drugs. The etiology of autism is not known and there is no drug for ameliorating basal symptoms of this disease. Some research was conducted to obtain an adequate rodent model of autism in which potential drugs can be studied. Therapeutic action of
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psychostimulant drugs in the attention deficit hyperactivity disorder (ADHD) are known for years, but because of their addictive properties, decision about their clinical use in a child is not easy. The precise recognition of their mechanism of action and determination of the maximal but safe doses should facilitate making the correct decision. Only about 70% children suffering from epilepsy are efficiently treated with one drug, while in the remaining the use of two or more drugs is necessary, which increases the the risk of side effects. Clinically more effective classical antiepileptic drugs can disturb cognitive functions in the child, therefore, on the basis of the present knowledge the experiments are under way with the aim of receiving drugs with strong anticonvulsant properties but without serious side effects. The introduction of efficient neuroprotective drugs, which may ameliorate secondary neuronal cell damage in various brain regions to the therapy is the main aim of numerous experimental works. At present it seems that neurotrophic factors can be useful but they must be administered centrally. Transplantations of transfected cells capable of producing neurotrophic factors or stem cells to the brain may be in the future an efficient method for improving brain function. PMID: 20297638 [PubMed - indexed for MEDLINE] Read more... [2008 Scientific descoveries selection]. [2008 Scientific descoveries selection]. Rev Med Chir Soc Med Nat Iasi. 2009 Jan-Mar;113(1):9-12 Authors: Rusu V PMID: 21495290 [PubMed - indexed for MEDLINE] Read more... Autistic phenotype from MEF2C knockout cells. Related Articles Autistic phenotype from MEF2C knockout cells. Science. 2009 Jan 9;323(5911):208 Authors: Lipton SA, Li H, Zaremba JD, McKercher SR, Cui J, Kang YJ, Nie Z, Soussou W, Talantova M, Okamoto S, Nakanishi N PMID: 19131610 [PubMed - indexed for MEDLINE] Read more... There is no evidence that . . . Related Articles There is no evidence that . . . Arch Ophthalmol. 2009 Jan;127(1):94-6 Authors: Kushner BJ PMID: 19139347 [PubMed - indexed for MEDLINE] Read more... An interview with Gabriela G. Cezar, D.V.M., Ph.D. by Glaser Vicki. Related Articles An interview with Gabriela G. Cezar, D.V.M., Ph.D. by Glaser Vicki. Assay Drug Dev Technol. 2009 Apr;7(2):105-9 Authors: Cezar GG PMID: 19505227 [PubMed - indexed for MEDLINE] Read more... Sera from children with autism alter proliferation of human neuronal progenitor cells exposed to oxidation. Related Articles Sera from children with autism alter proliferation of human neuronal progenitor cells exposed to oxidation. Neurotox Res. 2009 Jul;16(1):87-95 Authors: Mazur-Kolecka B, Cohen IL, Jenkins EC, Flory M, Merz G, Ted Brown W, Frackowiak J Abstract Altered brain development during embryogenesis and early postnatal life has been hypothesized to be responsible for the abnormal behaviors of people with autism. The specific genetic background that alters vulnerability to some environmental insults has been suggested in the etiology of autism; however, the specific pathomechanisms have not been identified. Recently, we showed that sera from children with autism alter the maturation of human neuronal progenitor cells (NPCs) in culture. Results suggest that pre-programmed neurogenesis, i.e., neuronal proliferation, migration, differentiation, growth, and circuit organization, can be affected differently by factors present in autistic sera. In this report, we tested the effect of autistic sera on the vulnerability of NPCs to oxidative stress-a recognized risk factor of autism. We found that mild oxidative stress reduced proliferation of differentiating NPCs but not immature NPCs. This decrease of proliferation was less prominent in cultures treated with sera from children with autism than from age-matched controls. These results suggest that altered response of NPCs to oxidative stress may play a role in the etiology of autism. PMID: 19526302 [PubMed - indexed for MEDLINE] Read more... MicroRNAs in adult and embryonic neurogenesis. Related Articles MicroRNAs in adult and embryonic neurogenesis. Neuromolecular Med. 2009;11(3):141-52 Authors: Liu C, Zhao X Abstract Neurogenesis is defined as a process that includes the proliferation of neural stem/progenitor cells (NPCs) and the differentiation of these cells into new neurons that integrate into the existing neuronal circuitry. MicroRNAs (miRNAs) are a recently discovered class of small non-protein coding RNA molecules implicated in a wide range of diverse gene regulatory mechanisms. More and more data demonstrate that numerous miRNAs are expressed in a spatially and temporally controlled manners in the nervous system, which suggests that miRNAs have
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important roles in the gene regulatory networks involved in both brain development and adult neural plasticity. This review summarizes the roles of miRNAs-mediated gene regulation in the nervous system with focus on neurogenesis in both embryonic and adult brains. PMID: 19598002 [PubMed - indexed for MEDLINE] Read more... MECP2 isoform-specific vectors with regulated expression for Rett syndrome gene therapy. Related Articles MECP2 isoform-specific vectors with regulated expression for Rett syndrome gene therapy. PLoS One. 2009;4(8):e6810 Authors: Rastegar M, Hotta A, Pasceri P, Makarem M, Cheung AY, Elliott S, Park KJ, Adachi M, Jones FS, Clarke ID, Dirks P, Ellis J Abstract BACKGROUND: Rett Syndrome (RTT) is an Autism Spectrum Disorder and the leading cause of mental retardation in females. RTT is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment. Our objective is to develop viral vectors for MECP2 gene transfer into Neural Stem Cells (NSC) and neurons suitable for gene therapy of Rett Syndrome. METHODOLOGY/PRINCIPAL FINDINGS: We generated self-inactivating (SIN) retroviral vectors with the ubiquitous EF1alpha promoter avoiding known silencer elements to escape stem-cell-specific viral silencing. High efficiency NSC infection resulted in long-term EGFP expression in transduced NSC and after differentiation into neurons. Infection with Myc-tagged MECP2-isoform-specific (E1 and E2) vectors directed MeCP2 to heterochromatin of transduced NSC and neurons. In contrast, vectors with an internal mouse Mecp2 promoter (MeP) directed restricted expression only in neurons and glia and not NSC, recapitulating the endogenous expression pattern required to avoid detrimental consequences of MECP2 ectopic expression. In differentiated NSC from adult heterozygous Mecp2(tm1.1Bird)+/- female mice, 48% of neurons expressed endogenous MeCP2 due to random inactivation of the X-linked Mecp2 gene. Retroviral MECP2 transduction with EF1alpha and MeP vectors rescued expression in 95-100% of neurons resulting in increased dendrite branching function in vitro. Insulated MECP2 isoform-specific lentiviral vectors show long-term expression in NSC and their differentiated neuronal progeny, and directly infect dissociated murine cortical neurons with high efficiency. CONCLUSIONS/SIGNIFICANCE: MeP vectors recapitulate the endogenous expression pattern of MeCP2 in neurons and glia. They have utility to study MeCP2 isoform-specific functions in vitro, and are effective gene therapy vectors for rescuing dendritic maturation of neurons in an ex vivo model of RTT. PMID: 19710912 [PubMed - indexed for MEDLINE] Read more... Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses. Related Articles Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses. J Physiol. 2009 Nov 1;587(Pt 21):5095-106 Authors: Medrihan L, Rohlmann A, Fairless R, Andrae J, Dring M, Missler M, Zhang W, Kilimann MW Abstract The development of neuronal networks in the brain requires the differentiation of functional synapses. Neurobeachin (Nbea) was identified as a putative regulator of membrane protein trafficking associated with tubulovesicular endomembranes and postsynaptic plasma membranes. Nbea is essential for evoked transmission at neuromuscular junctions, but its role in the central nervous system has not been characterized. Here, we have studied central synapses of a newly generated gene-trap knockout (KO) mouse line at embryonic day 18, because null-mutant mice are paralysed and die perinatally. Although the overall brain architecture was normal, we identified major abnormalities of synaptic function in mutant animals. In acute slices from the brainstem, both spontaneous excitatory and inhibitory postsynaptic currents were clearly reduced and failure rates of evoked inhibitory responses were markedly increased. In addition, the frequency of miniature excitatory and both the frequency and amplitudes of miniature inhibitory postsynaptic currents were severely diminished in KO mice, indicating a perturbation of both action potential-dependent and -independent transmitter release. Moreover, Nbea appears to be important for the formation and composition of central synapses because the area density of mature asymmetric contacts in the fetal brainstem was reduced to 30% of wild-type levels, and the expression levels of a subset of synaptic marker proteins were smaller than in littermate controls. Our data demonstrate for the first time a function of Nbea at central synapses that may be based on its presumed role in targeting membrane proteins to synaptic contacts, and are consistent with the 'excitatory-inhibitory imbalance' model of autism where Nbea gene rearrangements have been detected in some patients. PMID: 19723784 [PubMed - indexed for MEDLINE] Read more... Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders. Related Articles Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome
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and childhood neurodevelopmental disorders. Biol Psychiatry. 2010 May 1;67(9):887-94 Authors: Sakurai T, Ramoz N, Barreto M, Gazdoiu M, Takahashi N, Gertner M, Dorr N, Gama Sosa MA, De Gasperi R, Perez G, Schmeidler J, Mitropoulou V, Le HC, Lupu M, Hof PR, Elder GA, Buxbaum JD Abstract BACKGROUND: SLC25A12, a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production. METHODS: We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies. RESULTS: Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide(+) ratio, resulting in myelin defects. CONCLUSIONS: Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility. PMID: 20015484 [PubMed - indexed for MEDLINE] Read more... Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors. Related Articles Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors. J Neurosci. 2010 Mar 24;30(12):4197-209 Authors: Liu X, Hashimoto-Torii K, Torii M, Ding C, Rakic P Abstract During mitotic division in the telencephalic proliferative ventricular zone (VZ), the nuclei of the neural precursors move basally away from the ventricular surface for DNA synthesis, and apically return to the surface for mitotic division; a process known as interkinetic migration or "to-and-fro" nuclear translocation. The cell, which remains attached to the ventricular surface, either continues cycling, or exits the cycle and migrates to the subventricular zone or the developing cortical plate. Although gap junctions/hemichannels are known to modulate DNA synthesis via Ca(2+) waves, the role of Ca(+) oscillations and the mechanism of nuclear translocation in the VZ precursors are unclear. Here, we provide evidence that, during apical nuclear migration, VZ precursors display dynamic spontaneous Ca(2+) transients, which depend on functional gap junctions/hemichannels via ATP release and Ca(2+)-mobilizing messenger diffusion. Furthermore, we found that blocking gap junctions/hemichannels or short hairpin RNA-mediated knockdown of Cx43 (connexin 43) retards the apically directed interkinetic nuclear migration accompanied with changes in the nuclear length/width ratio. In addition, we demonstrated that blocking functional gap junctions/hemichannels induces phosphorylation of small GTPase cdc42 in the VZ precursors. The basal phase of interkinetic migration is much slower and appears to be mediated passively by mechanical forces after cell division. Our findings indicate that functional interference with gap junctions/hemichannels during embryonic development may lead to abnormal corticogenesis and dysfunction of the cerebral cortex in adult organisms. PMID: 20335455 [PubMed - indexed for MEDLINE] Read more... Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Related Articles Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. 2010 May 7;6(5):433-44 Authors: Liu C, Teng ZQ, Santistevan NJ, Szulwach KE, Guo W, Jin P, Zhao X Abstract Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNA methylation-mediated epigenetic mechanism. We have previously demonstrated that MBD1 deficiency impairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlying mechanism was unclear. Here, we show that MBD1 regulates the expression of several microRNAs in aNSCs and, specifically, that miR-184 is directly repressed by MBD1. High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency. We further found that miR-184 regulates the expression of Numblike (Numbl), a known regulator of brain development, by binding to the 3'-UTR of Numbl mRNA and affecting its translation. Expression of exogenous Numbl could rescue the aNSC defects that result from either miR-184 overexpression or MBD1 deficiency. Therefore, MBD1, miR-184, and Numbl form a regulatory network that helps control the balance between proliferation and differentiation of aNSCs. PMID: 20452318 [PubMed - indexed for MEDLINE]
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Read more... Role of H3K4 demethylases in complex neurodevelopmental diseases. Related Articles Role of H3K4 demethylases in complex neurodevelopmental diseases. Epigenomics. 2010 Jun;2(3):407-18 Authors: Wynder C, Stalker L, Doughty ML Abstract Significant neurological disorders can result from subtle perturbations of gene regulation that are often linked to epigenetic regulation. Proteins that regulate the methylation of lysine 4 of histone H3 (H3K4) and play a central role in epigenetic regulation, and mutations in genes encoding these enzymes have been identified in both autism and Rett syndrome. The H3K4 demethylases remove methyl groups from lysine 4 leading to loss of RNA polymerase binding and transcriptional repression. When these proteins are mutated, brain development is altered. Currently, little is known regarding how these gene regulators function at the genomic level. In this article, we will discuss findings that link H3K4 demethylases to neurodevelopment and neurological disease. PMID: 22121901 [PubMed - indexed for MEDLINE] Read more... Neural stem cell regulation, fibroblast growth factors, and the developmental origins of neuropsychiatric disorders. Related Articles Neural stem cell regulation, fibroblast growth factors, and the developmental origins of neuropsychiatric disorders. Front Neurosci. 2010;4 Authors: Stevens HE, Smith KM, Rash BG, Vaccarino FM Abstract There is increasing appreciation for the neurodevelopmental underpinnings of many psychiatric disorders. Disorders that begin in childhood such as autism, language disorders or mental retardation as well as adult-onset mental disorders may have origins early in neurodevelopment. Neural stem cells (NSCs) can be defined as self-renewing, multipotent cells that are present in both the embryonic and adult brain. Several recent research findings demonstrate that psychiatric illness may begin with abnormal specification, growth, expansion and differentiation of embryonic NSCs. For example, candidate susceptibility genes for schizophrenia, autism and major depression include the signaling molecule Disrupted In Schizophrenia-1 (DISC-1), the homeodomain gene engrailed-2 (EN-2), and several receptor tyrosine kinases, including brain-derived growth factor and fibroblast growth factors, all of which have been shown to play important roles in NSCs or neuronal precursors. We will discuss here stem cell biology, signaling factors that affect these cells, and the potential contribution of these processes to the etiology of neuropsychiatric disorders. Hypotheses about how some of these factors relate to psychiatric disorders will be reviewed. PMID: 20877431 [PubMed] Read more... Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. Related Articles Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. MBio. 2010;1(4) Authors: De Miranda J, Yaddanapudi K, Hornig M, Villar G, Serge R, Lipkin WI Abstract Maternal infection during pregnancy with a wide range of RNA and DNA viruses is associated with increased risk for schizophrenia and autism in their offspring. A common feature in these exposures is that virus replication induces innate immunity through interaction with Toll-like receptors (TLRs). We employed a mouse model wherein pregnant mice were exposed to polyinosinic-polycytidylic acid [poly(I C)], a synthetic, double-stranded RNA molecular mimic of replicating virus. Poly(I C) inhibited embryonic neuronal stem cell replication and population of the superficial layers of the neocortex by neurons. Poly(I C) also led to impaired neonatal locomotor development and abnormal sensorimotor gating responses in adult offspring. Using Toll-like receptor 3 (TLR3)-deficient mice, we established that these effects were dependent on TLR3. Inhibition of stem cell proliferation was also abrogated by pretreatment with the nonsteroidal anti-inflammatory drug (NSAID) carprofen, a cyclooxygenase (COX) inhibitor. Our findings provide insights into mechanisms by which maternal infection can induce subtle neuropathology and behavioral dysfunction, and they may suggest strategies for reducing the risk of neuropsychiatric disorders subsequent to prenatal exposures to pathogens and other triggers of innate immunity. PMID: 20941330 [PubMed - indexed for MEDLINE] Read more... Modeling Rett syndrome with stem cells. Related Articles Modeling Rett syndrome with stem cells. Cell. 2010 Nov 12;143(4):499-500 Authors: Walsh RM, Hochedlinger K Abstract The discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) raised the exciting possibility of modeling diseases with patient-specific cells. Marchetto et al. (2010) now use iPSC technology to generate, characterize, and treat an in vitro model for the autism spectrum disorder Rett syndrome.
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PMID: 21074040 [PubMed] Read more... A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Related Articles A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010 Nov 12;143(4):527-39 Authors: Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR Abstract Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. PMID: 21074045 [PubMed - indexed for MEDLINE] Read more... Excess of serotonin affects neocortical pyramidal neuron migration. Related Articles Excess of serotonin affects neocortical pyramidal neuron migration. Transl Psychiatry. 2011;1:e47 Authors: Riccio O, Jacobshagen M, Golding B, Vutskits L, Jabaudon D, Hornung JP, Dayer AG Abstract The serotonin transporter (SERT) is a key molecule involved in the homeostasis of extracellular levels of serotonin and is regulated developmentally. Genetic deletion of SERT in rodents increases extracellular levels of serotonin and affects cellular processes involved in neocortical circuit assembly such as barrel cortex wiring and cortical interneuron migration. Importantly, pharmacological blockade of SERT during brain development leads to phenotypes relevant to psychiatry in rodents and to an increased risk for autism spectrum disorders in humans. Furthermore, developmental adversity interacts with genetically-driven variations of serotonin function in humans and nonhuman primates to increase the risk for a variety of stress-related phenotypes. In this study, we investigate whether an excess of serotonin affects the migration of neocortical pyramidal neurons during development. Using in utero electroporation combined with time-lapse imaging to specifically monitor pyramidal neurons during late mouse embryogenesis, we show that an excess of serotonin reversibly affects the radial migration of pyramidal neurons. We further identify that the serotonin receptor 5-HT(6) is expressed in pyramidal neuron progenitors and that 5-HT(6) receptor activation replicates the effects of serotonin stimulation. Finally, we show that the positioning of superficial layer pyramidal neurons is altered in vivo in SERT knockout mice. Taken together, these results indicate that a developmental excess of serotonin decreases the migration speed of cortical pyramidal neurons, affecting a fundamental step in the assembly of neural circuits. These findings support the hypothesis that developmental dysregulation of serotonin homeostasis has detrimental effects on neocortical circuit formation and contributes to increased vulnerability to psychiatric disorders. PMID: 22833193 [PubMed - indexed for MEDLINE] Read more... Evaluation of Pax6 mutant rat as a model for autism. Related Articles Evaluation of Pax6 mutant rat as a model for autism. PLoS One. 2010;5(12):e15500 Authors: Umeda T, Takashima N, Nakagawa R, Maekawa M, Ikegami S, Yoshikawa T, Kobayashi K, Okanoya K, Inokuchi K, Osumi N Abstract Autism is a highly variable brain developmental disorder and has a strong genetic basis. Pax6 is a pivotal player in brain development and maintenance. It is expressed in embryonic and adult neural stem cells, in astrocytes in the entire central nervous system, and in neurons in the olfactory bulb, amygdala, thalamus, and cerebellum, functioning in highly context-dependent manners. We have recently reported that Pax6 heterozygous mutant (rSey(2)/+) rats with a spontaneous mutation in the Pax6 gene, show impaired prepulse inhibition (PPI). In the present study, we further examined behaviors of rSey(2)/+ rats and revealed that they exhibited abnormality in social interaction (more aggression and withdrawal) in addition to impairment in rearing activity and in fear-conditioned memory. Ultrasonic vocalization (USV) in rSey(2)+ rat pups was normal in male but abnormal in female. Moreover, treatment with clozapine successfully recovered the defects in sensorimotor gating function, but not in fear-conditioned memory. Taken together with our prior human genetic data and results in other literatures, rSey(2)/+ rats likely have some phenotypic components of autism. PMID: 21203536 [PubMed - indexed for MEDLINE] Read more...
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Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. Related Articles Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. J Child Psychol Psychiatry. 2011 Apr;52(4):504-16 Authors: Vaccarino FM, Urban AE, Stevens HE, Szekely A, Abyzov A, Grigorenko EL, Gerstein M, Weissman S Abstract The study of the developing brain has begun to shed light on the underpinnings of both early and adult onset neuropsychiatric disorders. Neuroimaging of the human brain across developmental time points and the use of model animal systems have combined to reveal brain systems and gene products that may play a role in autism spectrum disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder and many other neurodevelopmental conditions. However, precisely how genes may function in human brain development and how they interact with each other leading to psychiatric disorders is unknown. Because of an increasing understanding of neural stem cells and how the nervous system subsequently develops from these cells, we have now the ability to study disorders of the nervous system in a new way - by rewinding and reviewing the development of human neural cells. Induced pluripotent stem cells (iPSCs), developed from mature somatic cells, have allowed the development of specific cells in patients to be observed in real time. Moreover, they have allowed some neuronal-specific abnormalities to be corrected with pharmacological intervention in tissue culture. These exciting advances based on the use of iPSCs hold great promise for understanding, diagnosing and, possibly, treating psychiatric disorders. Specifically, examination of iPSCs from typically developing individuals will reveal how basic cellular processes and genetic differences contribute to individually unique nervous systems. Moreover, by comparing iPSCs from typically developing individuals and patients, differences at stem cell stages, through neural differentiation, and into the development of functional neurons may be identified that will reveal opportunities for intervention. The application of such techniques to early onset neuropsychiatric disorders is still on the horizon but has become a reality of current research efforts as a consequence of the revelations of many years of basic developmental neurobiological science. PMID: 21204834 [PubMed - indexed for MEDLINE] Read more... Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Related Articles Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell. 2011 Jan 7;8(1):59-71 Authors: Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI Abstract The majority of research on reactive oxygen species (ROS) has focused on their cellular toxicities. Stem cells generally have been thought to maintain low levels of ROS as a protection against these processes. However, recent studies suggest that ROS can also play roles as second messengers, activating normal cellular processes. Here, we investigated ROS function in primary brainderived neural progenitors. Somewhat surprisingly, we found that proliferative, self-renewing multipotent neural progenitors with the phenotypic characteristics of neural stem cells (NSC) maintained a high ROS status and were highly responsive to ROS stimulation. ROS-mediated enhancements in self-renewal and neurogenesis were dependent on PI3K/Akt signaling. Pharmacological or genetic manipulations that diminished cellular ROS levels also interfered with normal NSC and/or multipotent progenitor function both in vitro and in vivo. This study has identified a redoxmediated regulatory mechanism of NSC function that may have significant implications for brain injury, disease, and repair. PMID: 21211782 [PubMed - indexed for MEDLINE] Read more... c-Kit+ cells transplantation as a new treatment for autism, a novel hypothesis with important research and clinical implication. Related Articles c-Kit+ cells transplantation as a new treatment for autism, a novel hypothesis with important research and clinical implication. J Autism Dev Disord. 2011 Nov;41(11):1591-2 Authors: Ghanizadeh A PMID: 21225454 [PubMed - indexed for MEDLINE] Read more... Investigating synapse formation and function using human pluripotent stem cell-derived neurons. Related Articles Investigating synapse formation and function using human pluripotent stem cell-derived neurons. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3005-10 Authors: Kim JE, O'Sullivan ML, Sanchez CA, Hwang M, Israel MA, Brennand K, Deerinck TJ, Goldstein LS, Gage FH, Ellisman MH, Ghosh A Abstract A major goal of stem-cell research is to identify conditions that reliably regulate their differentiation into specific cell types. This goal is particularly important for human stem cells if they are to be used for in vivo transplantation or as a platform for drug development. Here we describe the establishment of procedures to direct the differentiation of human embryonic stem cells and human induced pluripotent stem cells into forebrain neurons that are capable of forming synaptic connections. In
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addition, HEK293T cells expressing Neuroligin (NLGN) 3 and NLGN4, but not those containing autism-associated mutations, are able to induce presynaptic differentiation in human induced pluripotent stem cell-derived neurons. We show that a mutant NLGN4 containing an in-frame deletion is unable to localize correctly to the cell surface when overexpressed and fails to enhance synapse formation in human induced pluripotent stem cell-derived neurons. These findings establish human pluripotent stem cell-derived neurons as a viable model for the study of synaptic differentiation and function under normal and disorder-associated conditions. PMID: 21278334 [PubMed - indexed for MEDLINE] Read more... Induced pluripotent stem cells: a new tool to confront the challenge of neuropsychiatric disorders. Related Articles Induced pluripotent stem cells: a new tool to confront the challenge of neuropsychiatric disorders. Neuropharmacology. 2011 Jun;60(7-8):1355-63 Authors: Vaccarino FM, Stevens HE, Kocabas A, Palejev D, Szekely A, Grigorenko EL, Weissman S Abstract Studies in the area of human brain development are critical as research on neurological and psychiatric disorders has advanced, revealing the origins of pathophysiology to be in the earliest developmental stages. Only with a more precise understanding of the genes and environments that influence the brain in these early stages can we address questions about the pathology, diagnosis, prevention and treatment of neuropsychiatric disorders of developmental origin, like autism, schizophrenia, and Tourette syndrome. A new approach for studying early developmental events is the use of induced pluripotent stem cells (iPSCs). These are cells with wide potential, similar to that of embryonic stem cells, derived from mature somatic cells. We review the protocols used to create iPSCs, including the most efficient and reliable reprogramming strategies available to date for generating iPSCs. In addition, we discuss how this new tool can be applied to neuropsychiatric research. The use of iPSCs can advance our understanding of how genes and gene products are dynamically involved in the formation of unique features of the human brain, and how aberrant genetic variation may interfere with its typical formation. The iPSC technology, if properly applied, can also address basic questions about neural differentiation such as how stem cells can be guided into general and specific neurodevelopmental pathways. Current work in neuropsychiatry with iPSCs derived from patients has focused on disorders with specific genetics deficits and those with less-defined origins; it has revealed previously unknown aspects of pathology and potential pharmacological interventions. These exciting advances based on the use of iPSCs hold promise for improving early diagnosis and, possibly, treatment of psychiatric disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID: 21371482 [PubMed - indexed for MEDLINE] Read more... Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Related Articles Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet. 2011 Jun 1;20(11):2103-15 Authors: Cheung AY, Horvath LM, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, Carrel L, Ellis J Abstract Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder that affects girls due primarily to mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). The majority of RTT patients carry missense and nonsense mutations leading to a hypomorphic MECP2, while null mutations leading to the complete absence of a functional protein are rare. MECP2 is an X-linked gene subject to random X-chromosome inactivation resulting in mosaic expression of mutant MECP2. The lack of human brain tissue motivates the need for alternative human cellular models to study RTT. Here we report the characterization of a MECP2 mutation in a classic female RTT patient involving rearrangements that remove exons 3 and 4 creating a functionally null mutation. To generate human neuron models of RTT, we isolated human induced pluripotent stem (hiPS) cells from RTT patient fibroblasts. RTT-hiPS cells retained the MECP2 mutation, are pluripotent and fully reprogrammed, and retained an inactive X-chromosome in a nonrandom pattern. Taking advantage of the latter characteristic, we obtained a pair of isogenic wild-type and mutant MECP2 expressing RTT-hiPS cell lines that retained this MECP2 expression pattern upon differentiation into neurons. Phenotypic analysis of mutant RTT-hiPS cell-derived neurons demonstrated a reduction in soma size compared with the isogenic control RTT-hiPS cell-derived neurons from the same RTT patient. Analysis of isogenic control and mutant hiPS cell-derived neurons represents a promising source for understanding the pathogenesis of RTT and the role of MECP2 in human neurons. PMID: 21372149 [PubMed - indexed for MEDLINE] Read more... Heads-up: new roles for the fragile X mental retardation protein in neural stem and progenitor cells. Related Articles Heads-up: new roles for the fragile X mental retardation protein in neural stem and progenitor cells.
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Genesis. 2011 Jun;49(6):424-40 Authors: Callan MA, Zarnescu DC Abstract Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function for Fragile X Mental Retardation Protein (FMRP), a selective RNA-binding protein with a demonstrated role in the localized translation of target mRNAs at synapses. Several recent studies provide compelling evidence for a new role of FMRP in the development of the nervous system, during neurogenesis. Using a multi-faceted approach and a variety of model systems ranging from cultured neurospheres and progenitor cells to in vivo Drosophila and mouse models these reports indicate that FMRP is required for neural stem and progenitor cell proliferation, differentiation, survival, as well as regulation of gene expression. Here we compare and contrast these recent reports and discuss the implications of FMRP's new role in embryonic and adult neurogenesis, including the development of novel therapeutic approaches to FXS and related neurological disorders such as autism. PMID: 21404421 [PubMed - indexed for MEDLINE] Read more... Profile of Gabriela G. Cezar. Interview by Kristie Nybo. Related Articles Profile of Gabriela G. Cezar. Interview by Kristie Nybo. Biotechniques. 2011 May;50(5):281 Authors: Cezar GG PMID: 21548887 [PubMed - indexed for MEDLINE] Read more... Looking back. Related Articles Looking back. Annu Rev Cell Dev Biol. 2011;27:1-23 Authors: Raff M Abstract In this Perspective, I review my scientific career, which began after I trained in medicine in Montreal and in neurology in Boston. I started in immunology in London with Avrion Mitchison, using antibodies against cell-surface antigens to study the development and functions of mouse T and B cells. The finding that antibody binding causes immunoglobulin on B cells to redistribute rapidly on the cell surface and be endocytosed transformed me from an immunologist into a cell biologist. I moved with Mitchison to University College London, where my colleagues and I used the antibody approach to study cells of the rodent nervous system, focusing on the intrinsic and extrinsic molecular mechanisms that control the development and behavior of myelinating glial cells-Schwann cells and oligodendrocytes. I retired from active research in 2002 and now spend much of my time on scientific advisory boards and thinking about autism. PMID: 21568709 [PubMed - indexed for MEDLINE] Read more... Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism. Related Articles Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism. Neurosci Lett. 2011 Jul 12;498(3):173-8 Authors: Mercier F, Cho Kwon Y, Kodama R Abstract Autism spectrum disorders are characterized by impaired social and communication skills and seem to result from altered neural development. We sought to determine whether the anatomy of the meninges and extracellular matrix (ECM) is altered in an animal model of autism, the BTBR T+ tf/J mouse. This mouse displays white matter tract anatomical defects and exhibits several symptoms of autism. Immunofluorescence cytochemistry for laminin, a major ECM marker, was performed on series of coronal sections of the adult BTBR T+ tf/J brain and the anatomy was analyzed in comparison to B6 wild type mice. Laminin immunoreactivity visualized meninges, blood vessels and the subventricular zone (SVZ) stem cell-associated ECM structures, which I have named fractones. All BTBR T+ tf/J mice observed showed the same forebrain defects. The lateral ventricle volume was severely reduced, the falx cerebri elongated, the arteries enlarged and the choroid plexus atrophied. Compared to B6 mice, fractone numbers in BTBR T+ tf/J mice were reduced by a factor three in the SVZ of the anterior portion of the lateral ventricle. This represents the primary neurogenic zone during adulthood. Fractones were reduced by a factor 1.5 in posterior portions of the lateral ventricle. Moreover, fractone size was reduced throughout the lateral ventricle SVZ. These results show hitherto unsuspected alterations in connective tissue/vasculature and associated ECM in the adult BTBR T+ tf/J mouse. The drastic changes of the connective tissue and ECM in the neurogenic zone of the lateral ventricle may contribute to incorrect neurogenesis during developmental and adult stages. PMID: 21600960 [PubMed - indexed for MEDLINE] Read more... Expression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes. Related Articles Expression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes. Schizophr Res. 2011 Aug;130(1-3):238-49 Authors: Katsel P, Tan W, Abazyan B, Davis KL, Ross C, Pletnikov MV, Haroutunian V Abstract Abnormalities in oligodendrocyte (OLG) differentiation and OLG gene expression deficit have been described in schizophrenia (SZ). Recent studies revealed a critical requirement for Disrupted-
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in-Schizophrenia 1 (DISC1) in neural development. Transgenic mice with forebrain restricted expression of mutant human DISC1 (hDISC1) are characterized by neuroanatomical and behavioral abnormalities reminiscent of some features of SZ. We sought to determine whether the expression of hDISC1 may influence the development of OLGs in this mouse model. OLG- and cell cycle-associated gene and protein expression were characterized in the forebrain of hDISC1 mice during different stages of neurodevelopment (E15 and P1 days) and in adulthood. The results suggest that the expression of hDISC1 exerts a significant influence on oligodendrocyte differentiation and function, evidenced by premature OLG differentiation and increased proliferation of their progenitors. Additional findings showed that neuregulin 1 and its receptors may be contributing factors to the observed upregulation of OLG genes. Thus, OLG function may be perturbed by mutant hDISC1 in a model system that provides new avenues for studying aspects of the pathogenesis of SZ. PMID: 21605958 [PubMed - indexed for MEDLINE] Read more... Right treatment, right patient? Related Articles Right treatment, right patient? Am J Nurs. 2011 Jun;111(6):72 Authors: Brown T PMID: 21613926 [PubMed - indexed for MEDLINE] Read more... Placental TNF- signaling in illness-induced complications of pregnancy. Related Articles Placental TNF- signaling in illness-induced complications of pregnancy. Am J Pathol. 2011 Jun;178(6):2802-10 Authors: Carpentier PA, Dingman AL, Palmer TD Abstract Maternal infections are implicated in a variety of complications during pregnancy, including pregnancy loss, prematurity, and increased risk of neurodevelopmental disorders in the child. Here, we show in mice that even mild innate immune activation by low-dose lipopolysaccharide in early pregnancy causes hemorrhages in the placenta and increases the risk of pregnancy loss. Surviving fetuses exhibit hypoxia in the brain and impaired fetal neurogenesis. Maternal Toll-like receptor 4 signaling is a critical mediator of this process, and its activation is accompanied by elevated proinflammatory cytokines in the placenta. We evaluated the role of tumor necrosis factor- (TNF-) signaling and show that TNF receptor 1 (TNFR1) is necessary for the illness-induced placental pathology, accompanying fetal hypoxia, and neuroproliferative defects in the fetal brain. We also show that placental TNFR1 in the absence of maternal TNFR1 is sufficient for placental pathology to develop and that a clinically relevant TNF- antagonist prevents placental pathology and fetal loss. Our observations suggest that the placenta is highly sensitive to proinflammatory signaling in early pregnancy and that TNF- is an effective target for preventing illness-related placental defects and related risks to the fetus and fetal brain development. PMID: 21641402 [PubMed - indexed for MEDLINE] Read more... Modeling the functional genomics of autism using human neurons. Related Articles Modeling the functional genomics of autism using human neurons. Mol Psychiatry. 2012 Feb;17(2):202-14 Authors: Konopka G, Wexler E, Rosen E, Mukamel Z, Osborn GE, Chen L, Lu D, Gao F, Gao K, Lowe JK, Geschwind DH Abstract Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD. PMID: 21647150 [PubMed - indexed for MEDLINE] Read more...
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A role for noncanonical microRNAs in the mammalian brain revealed by phenotypic differences in Dgcr8 versus Dicer1 knockouts and small RNA sequencing. Related Articles A role for noncanonical microRNAs in the mammalian brain revealed by phenotypic differences in Dgcr8 versus Dicer1 knockouts and small RNA sequencing. RNA. 2011 Aug;17(8):1489-501 Authors: Babiarz JE, Hsu R, Melton C, Thomas M, Ullian EM, Blelloch R Abstract Noncanonical microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs) are distinct subclasses of small RNAs that bypass the DGCR8/DROSHA Microprocessor but still require DICER1 for their biogenesis. What role, if any, they have in mammals remains unknown. To identify potential functional properties for these subclasses, we compared the phenotypes resulting from conditional deletion of Dgcr8 versus Dicer1 in post-mitotic neurons. The loss of Dicer1 resulted in an earlier lethality, more severe structural abnormalities, and increased apoptosis relative to that from Dgcr8 loss. Deep sequencing of small RNAs from the hippocampus and cortex of the conditional knockouts and control littermates identified multiple noncanonical microRNAs that were expressed at high levels in the brain relative to other tissues, including mirtrons and H/ACA snoRNA-derived small RNAs. In contrast, we found no evidence for endo-siRNAs in the brain. Taken together, our findings provide evidence for a diverse population of highly expressed noncanonical miRNAs that together are likely to play important functional roles in post-mitotic neurons. PMID: 21712401 [PubMed - indexed for MEDLINE] Read more... Valproic acid inhibits neural progenitor cell death by activation of NF-B signaling pathway and up-regulation of Bcl-XL. Related Articles Valproic acid inhibits neural progenitor cell death by activation of NF-B signaling pathway and up-regulation of Bcl-XL. J Biomed Sci. 2011;18(1):48 Authors: Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH Abstract BACKGROUND: At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis.Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. METHODS: Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C.) diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-B p65 was investigated by ChIP assay. RESULTS: In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IB and increased the nuclear translocation of NF-B, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL. CONCLUSION: To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IB and the activation of NF-B signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior. PMID: 21722408 [PubMed - indexed for MEDLINE] Read more... Autism or autisms? Finding the lowest common denominator. Related Articles Autism or autisms? Finding the lowest common denominator. Bol Asoc Med P R. 2010 Oct-Dec;102(4):17-24 Authors: Williams EL, Casanova MF Abstract Previous studies suggest the presence of a minicolumnopathy in autism. Minicolumnar abnormalities as well as certain migratory and proliferative defects, common to autism, may be rooted in the general mechanics of periventricular germinal cell division and maturation. Increased numbers of periventricular germinal cell/radial glia can be mimicked by a variety of different transgenic mouse models and environmental factors. These murine models and environmental factors illustrate how a fairly homogenous neuroanatomical phenotype can diverge at the genetic level. By first defining the lowest common denominator (i.e., the minicolumn) and then examining which pathways are vulnerable to involved genetic and environmental factors, we may gain a greater understanding of the pathophysiologic mechanisms underlying Autism Spectrum Conditions. PMID: 21766543 [PubMed - indexed for MEDLINE] Read more...
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Isolating nasal olfactory stem cells from rodents or humans. Related Articles Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp. 2011;(54) Authors: Girard SD, Devze A, Nivet E, Gepner B, Roman FS, Fron F Abstract The olfactory mucosa, located in the nasal cavity, is in charge of detecting odours. It is also the only nervous tissue that is exposed to the external environment and easily accessible in every living individual. As a result, this tissue is unique for anyone aiming to identify molecular anomalies in the pathological brain or isolate adult stem cells for cell therapy. Molecular abnormalities in brain diseases are often studied using nervous tissue samples collected post-mortem. However, this material has numerous limitations. In contrast, the olfactory mucosa is readily accessible and can be biopsied safely without any loss of sense of smell(1). Accordingly, the olfactory mucosa provides an "open window" in the adult human through which one can study developmental (e.g. autism, schizophrenia)(2-4) or neurodegenerative (e.g. Parkinson, Alzheimer) diseases(4,5). Olfactory mucosa can be used for either comparative molecular studies(4,6) or in vitro experiments on neurogenesis(3,7). The olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria(8-10). We recently developed a method to purify the adult stem cells located in the lamina propria and, after having demonstrated that they are closely related to bone marrow mesenchymal stem cells (BM-MSC), we named them olfactory ecto-mesenchymal stem cells (OE-MSC)(11). Interestingly, when compared to BM-MSCs, OE-MSCs display a high proliferation rate, an elevated clonogenicity and an inclination to differentiate into neural cells. We took advantage of these characteristics to perform studies dedicated to unveil new candidate genes in schizophrenia and Parkinson's disease(4). We and others have also shown that OE-MSCs are promising candidates for cell therapy, after a spinal cord trauma(12,13), a cochlear damage(14) or in an animal models of Parkinson's disease(15) or amnesia(16). In this study, we present methods to biopsy olfactory mucosa in rats and humans. After collection, the lamina propria is enzymatically separated from the epithelium and stem cells are purified using an enzymatic or a non-enzymatic method. Purified olfactory stem cells can then be either grown in large numbers and banked in liquid nitrogen or induced to form spheres or differentiated into neural cells. These stem cells can also be used for comparative omics (genomic, transcriptomic, epigenomic, proteomic) studies. PMID: 21876529 [PubMed indexed for MEDLINE] Read more... Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling. Related Articles Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15444-9 Authors: Herr KJ, Herr DR, Lee CW, Noguchi K, Chun J Abstract Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia, and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA(1-6), several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA(1) signaling involving stereotyped effects on NPCs: N-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo. Importantly, genetic removal or pharmacological inhibition of LPA(1) prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA(1) through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including G(i) and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA(1) signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury. PMID: 21878565 [PubMed - indexed for MEDLINE] Read more... RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. Related Articles RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One. 2011;6(9):e23356 Authors: Lin M, Pedrosa E, Shah A, Hrabovsky A, Maqbool S, Zheng D, Lachman HM Abstract Genome-wide expression analysis using next generation sequencing (RNA-Seq) provides an opportunity for in-depth molecular profiling of fundamental biological processes, such as cellular differentiation and malignant transformation. Differentiating human neurons derived from induced
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pluripotent stem cells (iPSCs) provide an ideal system for RNA-Seq since defective neurogenesis caused by abnormalities in transcription factors, DNA methylation, and chromatin modifiers lie at the heart of some neuropsychiatric disorders. As a preliminary step towards applying next generation sequencing using neurons derived from patient-specific iPSCs, we have carried out an RNA-Seq analysis on control human neurons. Dramatic changes in the expression of coding genes, long non-coding RNAs (lncRNAs), pseudogenes, and splice isoforms were seen during the transition from pluripotent stem cells to early differentiating neurons. A number of genes that undergo radical changes in expression during this transition include candidates for schizophrenia (SZ), bipolar disorder (BD) and autism spectrum disorders (ASD) that function as transcription factors and chromatin modifiers, such as POU3F2 and ZNF804A, and genes coding for cell adhesion proteins implicated in these conditions including NRXN1 and NLGN1. In addition, a number of novel lncRNAs were found to undergo dramatic changes in expression, one of which is HOTAIRM1, a regulator of several HOXA genes during myelopoiesis. The increase we observed in differentiating neurons suggests a role in neurogenesis as well. Finally, several lncRNAs that map near SNPs associated with SZ in genome wide association studies also increase during neuronal differentiation, suggesting that these novel transcripts may be abnormally regulated in a subgroup of patients. PMID: 21915259 [PubMed - indexed for MEDLINE] Read more... Modeling psychiatric disorders through reprogramming. Related Articles Modeling psychiatric disorders through reprogramming. Dis Model Mech. 2012 Jan;5(1):26-32 Authors: Brennand KJ, Gage FH Abstract Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely heritable complex genetic neurodevelopmental disorders. It is now possible to directly reprogram fibroblasts from psychiatric patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiate these disorder-specific hiPSCs into neurons. This means that researchers can generate nearly limitless quantities of live human neurons with genetic backgrounds that are known to result in psychiatric disorders, without knowing which genes are interacting to produce the disease state in each patient. With these new human-cell-based models, scientists can investigate the precise cell types that are affected in these disorders and elucidate the cellular and molecular defects that contribute to disease initiation and progression. Here, we present a short review of experiments using hiPSCs and other sophisticated in vitro approaches to study the pathways underlying psychiatric disorders. PMID: 21954066 [PubMed - indexed for MEDLINE] Read more... Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. Related Articles Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS One. 2011;6(9):e25255 Authors: Ananiev G, Williams EC, Li H, Chang Q Abstract Rett syndrome (RTT) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5-6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology. PMID: 21966470 [PubMed - indexed for MEDLINE] Read more... A complex between contactin-1 and the protein tyrosine phosphatase PTPRZ controls the development of oligodendrocyte precursor cells. Related Articles A complex between contactin-1 and the protein tyrosine phosphatase PTPRZ controls the development of oligodendrocyte precursor cells. Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17498-503 Authors: Lamprianou S, Chatzopoulou E, Thomas JL, Bouyain S, Harroch S Abstract The six members of the contactin (CNTN)
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family of neural cell adhesion molecules are involved in the formation and maintenance of the central nervous system (CNS) and have been linked to mental retardation and neuropsychiatric disorders such as autism. Five of the six CNTNs bind to the homologous receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ), but the biological roles of these interactions remain unclear. We report here the cocrystal structure of the carbonic anhydrase-like domain of PTPRZ bound to tandem Ig repeats of CNTN1 and combine these structural data with binding assays to show that PTPRZ binds specifically to CNTN1 expressed at the surface of oligodendrocyte precursor cells. Furthermore, analyses of glial cell populations in wild-type and PTPRZ-deficient mice show that the binding of PTPRZ to CNTN1 expressed at the surface of oligodendrocyte precursor cells inhibits their proliferation and promotes their development into mature oligodendrocytes. Overall, these results implicate the PTPRZ/CNTN1 complex as a previously unknown modulator of oligodendrogenesis. PMID: 21969550 [PubMed - indexed for MEDLINE] Read more... Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. Related Articles Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. J Med Genet. 2011 Dec;48(12):810-8 Authors: Willemsen MH, Valls A, Kirkels LA, Mastebroek M, Olde Loohuis N, Kos A, Wissink-Lindhout WM, de Brouwer AP, Nillesen WM, Pfundt R, Holder-Espinasse M, Valle L, Andrieux J, Coppens-Hofman MC, Rensen H, Hamel BC, van Bokhoven H, Aschrafi A, Kleefstra T Abstract BACKGROUND: MicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions. METHODS AND RESULTS: In three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery. CONCLUSIONS: This study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible. PMID: 22003227 [PubMed indexed for MEDLINE] Read more... Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. Related Articles Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One. 2011;6(10):e26203 Authors: Sheridan SD, Theriault KM, Reis SA, Zhou F, Madison JM, Daheron L, Loring JF, Haggarty SJ Abstract Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5' untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of
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the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology. PMID: 22022567 [PubMed - indexed for MEDLINE] Read more... Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Related Articles Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):E1070-9 Authors: Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ Abstract Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of Tsc1 loss in neural progenitor cells in Tsc1(cc) Nestin-rtTA(+) TetOp-cre(+) embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly, Tsc1-null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC. PMID: 22025691 [PubMed - indexed for MEDLINE] Read more... Neurexins and neuroligins: recent insights from invertebrates. Related Articles Neurexins and neuroligins: recent insights from invertebrates. Mol Neurobiol. 2011 Dec;44(3):426-40 Authors: Knight D, Xie W, Boulianne GL Abstract During brain development, each neuron must find and synapse with the correct pre- and postsynaptic partners. The complexity of these connections and the relatively large distances some neurons must send their axons to find the correct partners makes studying brain development one of the most challenging, and yet fascinating disciplines in biology. Furthermore, once the initial connections have been made, the neurons constantly remodel their dendritic and axonal arbours in response to changing demands. Neurexin and neuroligin are two cell adhesion molecules identified as important regulators of this process. The importance of these genes in the development and modulation of synaptic connectivity is emphasised by the observation that mutations in these genes in humans have been associated with cognitive disorders such as Autism spectrum disorders, Tourette syndrome and Schizophrenia. The present review will discuss recent advances in our understanding of the role of these genes in synaptic development and modulation, and in particular, we will focus on recent work in invertebrate models, and how these results relate to studies in mammals. PMID: 22037798 [PubMed - indexed for MEDLINE] Read more... Cellular reprogramming: recent advances in modeling neurological diseases. Related Articles Cellular reprogramming: recent advances in modeling neurological diseases. J Neurosci. 2011 Nov 9;31(45):16070-5 Authors: Ming GL, Brstle O, Muotri A, Studer L, Wernig M, Christian KM Abstract The remarkable advances in cellular reprogramming have made it possible to generate a renewable source of human neurons from fibroblasts obtained from skin samples of neonates and adults. As a result, we can now investigate the etiology of neurological diseases at the cellular level using neuronal populations derived from patients, which harbor the same genetic mutations thought to be relevant to the risk for pathology. Therapeutic implications include the ability to establish new humanized disease models for understanding mechanisms, conduct high-throughput screening for novel biogenic compounds to reverse or prevent the disease phenotype, identify and engineer genetic rescue of causal mutations, and develop patient-specific cellular replacement strategies. Although this field offers enormous potential for understanding and treating neurological disease, there are still many issues that must be addressed before we can fully exploit this technology. Here we summarize several recent studies presented at a symposium at the 2011 annual meeting of the Society for Neuroscience, which highlight innovative approaches to cellular reprogramming and how this revolutionary technique is being refined to model neurodevelopmental and neurodegenerative diseases, such as autism spectrum disorders, schizophrenia, familial dysautonomia, and Alzheimer's disease. PMID: 22072658 [PubMed
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- indexed for MEDLINE] Read more... Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-: implications for autism. Related Articles Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-: implications for autism. FASEB J. 2012 Mar;26(3):1040-51 Authors: Bailey AR, Hou H, Obregon DF, Tian J, Zhu Y, Zou Q, Nikolic WV, Bengtson M, Mori T, Murphy T, Tan J Abstract Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein (sAPP-) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP- in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP- could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP- and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP--overexpressing (TgsAPP-) mice displayed increased proportions of CD8(+) T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP- mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP- mice displayed decreased levels IFN-, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP- in some patients with autism, sAPP- could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation. PMID: 22085641 [PubMed - indexed for MEDLINE] Read more... Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Related Articles Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci. 2012 Feb;15(2):274-83 Authors: Goffin D, Allen M, Zhang L, Amorim M, Wang IT, Reyes AR, MercadoBerton A, Ong C, Cohen S, Hu L, Blendy JA, Carlson GC, Siegel SJ, Greenberg ME, Zhou Z Abstract Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation. PMID: 22119903 [PubMed - indexed for MEDLINE] Read more... Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Related Articles Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med. 2011 Dec;17(12):1657-62 Authors: Paca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Paca AM, Cord B, Palmer TD, Chikahisa S, Nishino S, Bernstein JA, Hallmayer J, Geschwind DH, Dolmetsch RE Abstract Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of
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cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome. PMID: 22120178 [PubMed - indexed for MEDLINE] Read more... Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. Related Articles Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. Mol Psychiatry. 2012 Dec;17(12):1261-71 Authors: Farra N, Zhang WB, Pasceri P, Eubanks JH, Salter MW, Ellis J Abstract Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Here, we describe the first characterization and neuronal differentiation of induced pluripotent stem (iPS) cells derived from Mecp2-deficient mice. Fully reprogrammed wild-type (WT) and heterozygous female iPS cells express endogenous pluripotency markers, reactivate the X-chromosome and differentiate into the three germ layers. We directed iPS cells to produce glutamatergic neurons, which generated action potentials and formed functional excitatory synapses. iPS cell-derived neurons from heterozygous Mecp2(308) mice showed defects in the generation of evoked action potentials and glutamatergic synaptic transmission, as previously reported in brain slices. Further, we examined electrophysiology features not yet studied with the RTT iPS cell system and discovered that MeCP2-deficient neurons fired fewer action potentials, and displayed decreased action potential amplitude, diminished peak inward currents and higher input resistance relative to WT iPS-derived neurons. Deficiencies in action potential firing and inward currents suggest that disturbed Na(+) channel function may contribute to the dysfunctional RTT neuronal network. These phenotypes were additionally confirmed in neurons derived from independent WT and hemizygous mutant iPS cell lines, indicating that these reproducible deficits are attributable to MeCP2 deficiency. Taken together, these results demonstrate that neuronally differentiated MeCP2-deficient iPS cells recapitulate deficits observed previously in primary neurons, and these identified phenotypes further illustrate the requirement of MeCP2 in neuronal development and/or in the maintenance of normal function. By validating the use of iPS cells to delineate mechanisms underlying RTT pathogenesis, we identify deficiencies that can be targeted for in vitro translational screens. PMID: 22230884 [PubMed - indexed for MEDLINE] Read more... Derivation of autism spectrum disorder-specific induced pluripotent stem cells from peripheral blood mononuclear cells. Related Articles Derivation of autism spectrum disorder-specific induced pluripotent stem cells from peripheral blood mononuclear cells. Neurosci Lett. 2012 May 10;516(1):9-14 Authors: DeRosa BA, Van Baaren JM, Dubey GK, Lee JM, Cuccaro ML, Vance JM, Pericak-Vance MA, Dykxhoorn DM Abstract Induced pluripotent stem cells (iPSCs) hold tremendous potential both as a biological tool to uncover the pathophysiology of disease by creating relevant cell models and as a source of stem cells for cell-based therapeutic applications. Typically, iPSCs have been derived by the transgenic overexpression of transcription factors associated with progenitor cell or stem cell function in fibroblasts derived from skin biopsies. However, the need for skin punch biopsies to derive fibroblasts for reprogramming can present a barrier to study participation among certain populations of individuals, including children with autism spectrum disorders (ASDs). In addition, the acquisition of skin punch biopsies in non-clinic settings presents a challenge. One potential mechanism to avoid these limitations would be the use of peripheral blood mononuclear cells (PBMCs) as the source of the cells for reprogramming. In this article we describe, for the first time, the derivation of iPSC lines from PBMCs isolated from the whole blood of autistic children, and their subsequent differentiation in GABAergic neurons. PMID: 22405972 [PubMed - indexed for MEDLINE] Read more... Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. Related Articles Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. Genes Brain Behav. 2012 Jul;11(5):513-23 Authors: Uutela M, Lindholm J, Louhivuori V, Wei H, Louhivuori LM, Pertovaara A, Akerman K, Castrn E, Castrn ML Abstract Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age-dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or
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central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus-dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype. PMID: 22435671 [PubMed - indexed for MEDLINE] Read more... All-trans-retinoid acid induces the differentiation of encapsulated mouse embryonic stem cells into GABAergic neurons. Related Articles All-trans-retinoid acid induces the differentiation of encapsulated mouse embryonic stem cells into GABAergic neurons. Differentiation. 2012 Jun;83(5):233-41 Authors: Addae C, Yi X, Gernapudi R, Cheng H, Musto A, Martinez-Ceballos E Abstract Embryonic stem (ES) cells are pluripotent cells that can differentiate into all three main germ layers: endoderm, mesoderm, and ectoderm. Although a number of methods have been developed to differentiate ES cells into neuronal phenotypes such as sensory and motor neurons, the efficient generation of GABAergic interneurons from ES cells still presents an ongoing challenge. Because the main output of inhibitory GABAergic interneurons is the gamma-aminobutyric-acid (GABA), a neurotransmitter whose controlled homeostasis is required for normal brain function, the efficient generation in culture of functional interneurons may have future implications on the treatment of neurological disorders such as epilepsy, autism, and schizophrenia. The goal of this work was to examine the generation of GABAergic neurons from mouse ES cells by comparing an embryoid body-based methodology versus a hydrogel-based encapsulation protocol that involves the use of all-trans-retinoid acid (RA). We observed that (1) there was a 2-fold increase in neuronal differentiation in encapsulated versus non-encapsulated cells and (2) there was an increase in the specificity for interneuronal differentiation in encapsulated cells, as assessed by mRNA expression and electrophysiology approaches. Furthermore, our results indicate that most of the neurons obtained from encapsulated mouse ES cells are GABA-positive (87%). Thus, these results suggest that combining encapsulation of ES cells and RA treatment provide a more efficient and scalable differentiation strategy for the generation in culture of functional GABAergic interneurons. This technology may have implications for future cell replacement therapies and the treatment of CNS disorders. PMID: 22466603 [PubMed - indexed for MEDLINE] Read more... Modeling psychiatric disorders at the cellular and network levels. Related Articles Modeling psychiatric disorders at the cellular and network levels. Mol Psychiatry. 2012 Dec;17(12):1239-53 Authors: Brennand KJ, Simone A, Tran N, Gage FH Abstract Although psychiatric disorders such as autism spectrum disorders, schizophrenia and bipolar disorder affect a number of brain regions and produce a complex array of clinical symptoms, basic phenotypes likely exist at the level of single neurons and simple networks. Being highly heritable, it is hypothesized that these disorders are amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or induced neurons from fibroblasts, limitless numbers of live human neurons can now be generated from patients with a genetic background permissive to the disease state. We predict that cell-based studies will ultimately contribute to our understanding of the initiation, progression and treatment of these psychiatric disorders. PMID: 22472874 [PubMed - indexed for MEDLINE] Read more... Neurodevelopmental model of schizophrenia: update 2012. Related Articles Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry. 2012 Dec;17(12):1228-38 Authors: Rapoport JL, Giedd JN, Gogtay N Abstract The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood-onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole-population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain
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imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments. PMID: 22488257 [PubMed - indexed for MEDLINE] Read more... Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? Related Articles Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? J Biomed Biotechnol. 2012;2012:480289 Authors: Siniscalco D, Sapone A, Cirillo A, Giordano C, Maione S, Antonucci N Abstract Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease. PMID: 22496609 [PubMed indexed for MEDLINE] Read more... China's stem-cell rules go unheeded. Related Articles China's stem-cell rules go unheeded. Nature. 2012 Apr 12;484(7393):149-50 Authors: Cyranoski D PMID: 22498601 [PubMed - indexed for MEDLINE] Read more... Fragile X Protein is required for inhibition of insulin signaling and regulates glial-dependent neuroblast reactivation in the developing brain. Related Articles Fragile X Protein is required for inhibition of insulin signaling and regulates glial-dependent neuroblast reactivation in the developing brain. Brain Res. 2012 Jun 26;1462:151-61 Authors: Callan MA, Clements N, Ahrendt N, Zarnescu DC Abstract Fragile X syndrome (FXS) is the most common form of inherited mental disability and known cause of autism. It is caused by loss of function for the RNA binding protein FMRP, which has been demonstrated to regulate several aspects of RNA metabolism including transport, stability and translation at synapses. Recently, FMRP has been implicated in neural stem cell proliferation and differentiation both in cultured neurospheres as well as in vivo mouse and fly models of FXS. We have previously shown that FMRP deficient Drosophila neuroblasts upregulate Cyclin E, prematurely exit quiescence, and overproliferate to generate on average 16% more neurons. Here we further investigate FMRP's role during early development using the Drosophila larval brain as a model. Using tissue specific RNAi we find that FMRP is required sequentially, first in neuroblasts and then in glia, to regulate exit from quiescence as measured by Cyclin E expression in the brain. Furthermore, we tested the hypothesis that FMRP controls brain development by regulating the insulin signaling pathway, which has been recently shown to regulate neuroblast exit from quiescence. Our data indicate that phosphoAkt, a readout of insulin signaling, is upregulated in dFmr1 brains at the time when FMRP is required in glia for neuroblast reactivation. In addition, dFmr1 interacts genetically with dFoxO, a transcriptional regulator of insulin signaling. Our results provide the first evidence that FMRP is required in vivo, in glia for neuroblast reactivation and suggest that it may do so by regulating the output of the insulin signaling pathway. This article is part of a Special Issue entitled: RNA-Binding Proteins. PMID: 22513101 [PubMed - indexed for MEDLINE] Read more... Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Related Articles Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplant. 2012;21 Suppl 1:S79-90 Authors: Sharma A, Gokulchandran N, Chopra G, Kulkarni P, Lohia M, Badhe P, Jacob VC Abstract Neurological disorders such as muscular dystrophy, cerebral palsy, and injury to the brain and spine currently have no known definitive treatments or cures. A study was carried out on 71 children suffering from such incurable neurological
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disorders and injury. They were intrathecally and intramuscularly administered autologous bone marrow-derived mononuclear cells. Assessment after transplantation showed neurological improvements in muscle power and a shift on assessment scales such as FIM and Brooke and Vignos scale. Further, imaging and electrophysiological studies also showed significant changes in selective cases. On an average follow-up of 15 1 months, overall 97% muscular dystrophy cases showed subjective and functional improvement, with 2 of them also showing changes on MRI and 3 on EMG. One hundred percent of the spinal cord injury cases showed improvement with respect to muscle strength, urine control, spasticity, etc. Eighty-five percent of cases of cerebral palsy cases showed improvements, out of which 75% reported improvement in muscle tone and 50% in speech among other symptoms. Eighty-eight percent of cases of other incurable neurological disorders such as autism, Retts Syndrome, giant axonal neuropathy, etc., also showed improvement. No significant adverse events were noted. The results show that this treatment is safe, efficacious, and also improves the quality of life of children with incurable neurological disorders and injury. PMID: 22507683 [PubMed indexed for MEDLINE] Read more... Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. Related Articles Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J Neurosci. 2012 Apr 25;32(17):5880-90 Authors: Amiri A, Cho W, Zhou J, Birnbaum SG, Sinton CM, McKay RM, Parada LF Abstract Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors. PMID: 22539849 [PubMed - indexed for MEDLINE] Read more... Signaling defects in iPSC-derived fragile X premutation neurons. Related Articles Signaling defects in iPSC-derived fragile X premutation neurons. Hum Mol Genet. 2012 Sep 1;21(17):3795-805 Authors: Liu J, Koscielska KA, Cao Z, Hulsizer S, Grace N, Mitchell G, Nacey C, Githinji J, McGee J, Garcia-Arocena D, Hagerman RJ, Nolta J, Pessah IN, Hagerman PJ Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders. PMID: 22641815 [PubMed - indexed for MEDLINE] Read more... Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder. Related Articles Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder. Hum Mol Genet. 2012 Sep 15;21(18):4030-7 Authors: Etain B, Dumaine A, Bellivier F, Pagan C, Francelle L, Goubran-Botros H, Moreno S, Deshommes J, Moustafa K, Le Dudal K, Mathieu F, Henry C, Kahn JP, Launay JM, Mhleisen TW, Cichon S, Bourgeron T, Leboyer M, Jamain S Abstract Patients affected by bipolar disorder (BD)
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frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD. PMID: 22694957 [PubMed - indexed for MEDLINE] Read more... Modeling neurodevelopmental disorders using human neurons. Related Articles Modeling neurodevelopmental disorders using human neurons. Curr Opin Neurobiol. 2012 Oct;22(5):785-90 Authors: Chailangkarn T, Acab A, Muotri AR Abstract The cellular and molecular mechanisms of neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The unavailability of live patient neurons for research, however, has represented a major obstacle in the elucidation of the disease etiologies. Recently, the development of induced pluripotent stem cell (iPSC) technology allows for the generation of human neurons from somatic cells of patients. We review ongoing studies using iPSCs as an approach to model neurodevelopmental disorders, the promise and caveats of this technique and its potential for drug screening. The reproducible findings of relevant phenotypes in Rett syndrome iPSC-derived neurons suggest that iPSC technology offers a novel and unique opportunity for the understanding of and the development of therapeutics for other autism spectrum disorders. PMID: 22717528 [PubMed - indexed for MEDLINE] Read more... Disrupted ERK signaling during cortical development leads to abnormal progenitor proliferation, neuronal and network excitability and behavior, modeling human neuro-cardio-facial-cutaneous and related syndromes. Related Articles Disrupted ERK signaling during cortical development leads to abnormal progenitor proliferation, neuronal and network excitability and behavior, modeling human neuro-cardio-facial-cutaneous and related syndromes. J Neurosci. 2012 Jun 20;32(25):8663-77 Authors: Pucilowska J, Puzerey PA, Karlo JC, Galn RF, Landreth GE Abstract Genetic disorders arising from copy number variations in the ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases or mutations in their upstream regulators that result in neuro-cardio-facialcutaneous syndromes are associated with developmental abnormalities, cognitive deficits, and autism. We developed murine models of these disorders by deleting the ERKs at the beginning of neurogenesis and report disrupted cortical progenitor generation and proliferation, which leads to altered cytoarchitecture of the postnatal brain in a gene-dosedependent manner. We show that these changes are due to ERK-dependent dysregulation of cyclin D1 and p27(Kip1), resulting in cell cycle elongation, favoring neurogenic over self-renewing divisions. The precocious neurogenesis causes premature progenitor pool depletion, altering the number and distribution of pyramidal neurons. Importantly, loss of ERK2 alters the intrinsic excitability of cortical neurons and contributes to perturbations in global network activity. These changes are associated with elevated anxiety and impaired working and hippocampal-dependent memory in these mice. This study provides a novel mechanistic insight into the basis of cortical malformation which may provide a potential link to cognitive deficits in individuals with altered ERK activity. PMID: 22723706 [PubMed indexed for MEDLINE] Read more... RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Related Articles RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum Mol Genet. 2012 Oct 1;21(19):4171-86 Authors: Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C, Gao F, Parikshak N, Konopka G, Geschwind DH Abstract RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed
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A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons. PMID: 22730494 [PubMed - indexed for MEDLINE] Read more... Cellular reprogramming: a novel tool for investigating autism spectrum disorders. Related Articles Cellular reprogramming: a novel tool for investigating autism spectrum disorders. Trends Mol Med. 2012 Aug;18(8):463-71 Authors: Kim KY, Jung YW, Sullivan GJ, Chung L, Park IH Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interaction and communication, as well as the manifestation of stereotyped behaviors. Despite much effort, ASDs are not yet fully understood. Advanced genetics and genomics technologies have recently identified novel ASD genes, and approaches using genetically engineered murine models or postmortem human brain have facilitated understanding ASD. Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) provides unprecedented opportunities in generating human disease models. Here, we present an overview of applying iPSCs in developing cellular models for understanding ASD. We also discuss future perspectives in the use of iPSCs as a source of cell therapy and as a screening platform for identifying small molecules with efficacy for alleviating ASD. PMID: 22771169 [PubMed - indexed for MEDLINE] Read more... Modeling an autism risk factor in mice leads to permanent immune dysregulation. Related Articles Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81 Authors: Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH Abstract Increasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4(+) TCR(+) Foxp3(+) CD25(+) T regulatory cells, increased IL-6 and IL-17 production by CD4(+) T cells, and elevated levels of peripheral Gr-1(+) cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor. PMID: 22802640 [PubMed - indexed for MEDLINE] Read more... Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3/-catenin pathway. Related Articles Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3/-catenin pathway. Neuropharmacology. 2012 Nov;63(6):1028-41 Authors: Go HS, Kim KC, Choi CS, Jeon SJ, Kwon KJ, Han SH, Lee J, Cheong JH, Ryu JH, Kim CH, Ko KH, Shin CY Abstract Autism is a spectrum of neurodevelopmental disorders characterized by social isolation and lack of interaction. Anatomically, autism patients often show macrocephaly and high neuronal density. To investigate the mechanism underlying the higher neuronal populations seen in ASD, we subcutaneously injected VPA (400 mg/kg) into pregnant
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Sprague-Dawley rats on E12, an animal model often used in ASD study. Alternatively, cultured rat neural progenitor cells were treated with VPA. Until E18, VPA induced NPC proliferation and delayed neurogenesis in fetal brain, but the subsequent differentiation of NPCs to neurons increased brain neuronal density afterward. Similar findings were observed with NPCs treated with VPA in vitro. At a molecular level, VPA enhanced Wnt1 expression and activated the GSK-3/-catenin pathway. Furthermore, inhibition of this pathway attenuated the effects of VPA. The findings of this study suggest that an altered developmental process underlies the macrocephaly and abnormal brain structure observed in the autistic brain. PMID: 22841957 [PubMed - indexed for MEDLINE] Read more... Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons. Related Articles Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons. Stem Cells. 2012 Oct;30(10):2128-39 Authors: Yazdani M, Deogracias R, Guy J, Poot RA, Bird A, Barde YA Abstract Mutations in the gene encoding the methyl-CpG-binding protein MECP2 are the major cause of Rett syndrome, an autism spectrum disorder mainly affecting young females. MeCP2 is an abundant chromatin-associated protein, but how and when its absence begins to alter brain function is still far from clear. Using a stem cell-based system allowing the synchronous differentiation of neuronal progenitors, we found that in the absence of MeCP2, the size of neuronal nuclei fails to increase at normal rates during differentiation. This is accompanied by a marked decrease in the rate of ribonucleotide incorporation, indicating an early role of MeCP2 in regulating total gene transcription, not restricted to selected mRNAs. We also found that the levels of brain-derived neurotrophic factor (BDNF) were decreased in mutant neurons, while those of the presynaptic protein synaptophysin increased at similar rates in wild-type and mutant neurons. By contrast, nuclear size, transcription rates, and BDNF levels remained unchanged in astrocytes lacking MeCP2. Re-expressing MeCP2 in mutant neurons rescued the nuclear size phenotype as well as BDNF levels. These results reveal a new role of MeCP2 in regulating overall RNA synthesis in neurons during the course of their maturation, in line with recent findings indicating a reduced nucleolar size in neurons of the developing brain of mice lacking Mecp2. PMID: 22865604 [PubMed - indexed for MEDLINE] Read more... CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Related Articles CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol. 2012 Sep;14(9):911-23 Authors: Ricciardi S, Ungaro F, Hambrock M, Rademacher N, Stefanelli G, Brambilla D, Sessa A, Magagnotti C, Bachi A, Giarda E, Verpelli C, Kilstrup-Nielsen C, Sala C, Kalscheuer VM, Broccoli V Abstract Mutations of the cyclindependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phosphomutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans. PMID: 22922712 [PubMed - indexed for MEDLINE] Read more... Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. Related Articles Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. PLoS One. 2012;7(8):e44017 Authors: Lin M, Hrabovsky A, Pedrosa E, Wang T, Zheng D, Lachman HM Abstract Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons
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that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process - allele-biased expression - could have therapeutic implications. PMID: 22952857 [PubMed - indexed for MEDLINE] Read more... Stem cells and modeling of autism spectrum disorders. Related Articles Stem cells and modeling of autism spectrum disorders. Exp Neurol. 2012 Oct 2; Authors: Freitas BC, Trujillo CA, Carromeu C, Yusupova M, Herai RH, Muotri AR Abstract Human neurons, generated from reprogrammed somatic cells isolated from live patients, bring a new perspective on the understanding of Autism Spectrum Disorders (ASD). The new technology can nicely complement other models for basic research and the development of therapeutic compounds aiming to revert or ameliorate the condition. Here, we discuss recent advances on the use of stem cells and other models to study ASDs, as well as their limitations, implications and future perspectives. PMID: 23036599 [PubMed - as supplied by publisher] Read more... [Autism, stem cells, and magical powder]. Related Articles [Autism, stem cells, and magical powder]. Rev Med Suisse. 2012 Sep 19;8(354):1795 Authors: Mauron A PMID: 23097920 [PubMed - indexed for MEDLINE] Read more... Intranasal Treatment of Central Nervous System Dysfunction in Humans. Related Articles Intranasal Treatment of Central Nervous System Dysfunction in Humans. Pharm Res. 2012 Nov 8; Authors: Chapman CD, Frey WH, Craft S, Danielyan L, Hallschmid M, Schith HB, Benedict C Abstract One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke. PMID: 23135822 [PubMed - as supplied by publisher] Read more... Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex. Related Articles Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex. Neuropharmacology. 2013 Apr;67:1-7 Authors: Cambiaghi M, Cursi M, Magri L, Castoldi V, Comi G, Minicucci F, Galli R, Leocani L Abstract Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing.
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PMID: 23159330 [PubMed - in process] Read more... Genomic and proteomic advances in autism research. Related Articles Genomic and proteomic advances in autism research. Electrophoresis. 2012 Dec;33(24):3653-8 Authors: Maurer MH Abstract Recent studies suggest that adult neural stem cells (NSCs) may play a role in the pathogenesis of a number of the developmental disorders subsumed under the term autism spectrum disorders (ASD) that have in common impaired social interaction, communication deficits, and stereotypical behavior or interests. Since there is no "unifying hypothesis" about the etiology and pathogenesis of ASD, several factors have been associated with ASD, including genetic factors, physical co-morbidity, disturbances of brain structure and function, biochemical anomalies, cognitive impairment, and disorders of speech and emotional development, mostly the lack of empathy. Most of disturbances of brain interconnectivity are regarded as main problem in autism. Since NSCs have a distinct life cycle in the mammalian brain consisting of proliferation, migration, arborization, integration into existing neuronal circuits, and myelinization, disturbances in NSCs differentiation is thought to be deleterious. In the current review, I will summarize the results of genomic and proteomic studies finding susceptibility genes and proteins for autism with regard to NSCs differentiation and maturation. PMID: 23160986 [PubMed - indexed for MEDLINE] Read more... Dense-map genome scan for dyslexia supports loci at 4q13, 16p12, 17q22; suggests novel locus at 7q36. Related Articles Dense-map genome scan for dyslexia supports loci at 4q13, 16p12, 17q22; suggests novel locus at 7q36. Genes Brain Behav. 2013 Feb;12(1):56-69 Authors: Field LL, Shumansky K, Ryan J, Truong D, Swiergala E, Kaplan BJ Abstract Analysis of genetic linkage to dyslexia was performed using 133,165 array-based SNPs genotyped in 718 persons from 101 dyslexia-affected families. Results showed five linkage peaks with lod scores >2.3 (4q13.1, 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). Of these five regions, three have been previously implicated in dyslexia (4q13.1, 16p12.1, and 17q22), three have been implicated in attention-deficit hyperactivity disorder (ADHD, which highly co-occurs with dyslexia; 4q13.1, 7q36.3, 16p12.1) and four have been implicated in autism (a condition characterized by language deficits; 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). These results highlight the reproducibility of dyslexia linkage signals, even without formally significant lod scores, and suggest dyslexia predisposing genes with relatively major effects and locus heterogeneity. The largest lod score (2.80) occurred at 17q22 within the MSI2 gene, involved in neuronal stem cell lineage proliferation. Interestingly, the 4q13.1 linkage peak (lod 2.34) occurred immediately upstream of the LPHN3 gene, recently reported both linked and associated with ADHD. Separate analyses of larger pedigrees revealed lods >2.3 at 1-3 regions per family; one family showed strong linkage (lod 2.9) to a known dyslexia locus (18p11) not detected in our overall data, demonstrating the value of analyzing single large pedigrees. Association analysis identified no SNPs with genome-wide significance, although a borderline significant SNP (P = 6 10(-7)) occurred at 5q35.1 near FGF18, involved in laminar positioning of cortical neurons during development. We conclude that dyslexia genes with relatively major effects exist, are detectable by linkage analysis despite genetic heterogeneity, and show substantial overlapping predisposition with ADHD and autism. PMID: 23190410 [PubMed - indexed for MEDLINE] Read more... Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background. Related Articles Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background. Toxicol Sci. 2013 Mar;132(1):196-210 Authors: Napoli E, Hung C, Wong S, Giulivi C Abstract Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether [BDE-47] and 2,2',4,5'-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC
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and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain. PMID: 23288049 [PubMed - indexed for MEDLINE] Read more... Modeling Timothy syndrome with iPS cells. Related Articles Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res. 2013 Feb;6(1):1-9 Authors: Yazawa M, Dolmetsch RE Abstract Genetic mutations in ion channel genes that are associated with cardiac arrhythmias have been identified over the past several decades. However, little is known about the pathophysiological processes. An important limitation has been the difficulty of using human cardiomyocytes to study arrhythmias and identify drugs. To circumvent this issue, we have developed a method using human-induced pluripotent stem cells to generate cardiomyocytes from individuals with Timothy syndrome (TS), a genetic disorder characterized by QT prolongation, ventricular tachycardia, and autism. The TS ventricular-like cardiomyocytes exhibit deficits in contraction, electrical signaling, and calcium handling, as revealed by live cell imaging and electrophysiological studies. We tested candidate drugs in TS cardiomyocytes and found that roscovitine could successfully rescue these cellular phenotypes. The use of a human cellular model of cardiac arrhythmias provides a useful new platform not only to study disease mechanisms but also to develop new therapies to treat cardiac arrhythmias. PMID: 23299782 [PubMed - indexed for MEDLINE] Read more... Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Related Articles Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci. 2013 Feb;16(2):201-9 Authors: Krey JF, Paca SP, Shcheglovitov A, Yazawa M, Schwemberger R, Rasmusson R, Dolmetsch RE Abstract L-type voltage gated calcium channels have an important role in neuronal development by promoting dendritic growth and arborization. A point mutation in the gene encoding Ca(V)1.2 causes Timothy syndrome, a neurodevelopmental disorder associated with autism spectrum disorders (ASDs). We report that channels with the Timothy syndrome alteration cause activity-dependent dendrite retraction in rat and mouse neurons and in induced pluripotent stem cell (iPSC)-derived neurons from individuals with Timothy syndrome. Dendrite retraction was independent of calcium permeation through the mutant channel, was associated with ectopic activation of RhoA and was inhibited by overexpression of the channel-associated GTPase Gem. These results suggest that Ca(V)1.2 can activate RhoA signaling independently of Ca(2+) and provide insights into the cellular basis of Timothy syndrome and other ASDs. PMID: 23313911 [PubMed - indexed for MEDLINE] Read more... Meeting report: using stem cells for biological and therapeutics discovery in mental illness, April 2012. Related Articles Meeting report: using stem cells for biological and therapeutics discovery in mental illness, April 2012. Stem Cells Transl Med. 2013 Mar;2(3):217-22 Authors: Panchision DM Abstract This report synthesizes the discussions during a workshop convened April 24-25, 2012, by the National Institute of Mental Health and the Foundation for the NIH in Bethesda, Maryland, that focused on progress and challenges in the use of patient-derived reprogrammed cells for basic biological discovery, target identification, screening, and drug development for mental illnesses such as schizophrenia, bipolar disorder, and autism spectrum disorders. The workshop revealed that the greatest progress has been made in reprogramming methods and agreed-upon standards for validating the resulting induced pluripotent stem cell lines. However, challenges remain in several areas, including efficiently generating and validating specific neural cell types with respect to regional identity, establishing assays with predictive validity to mental illness pathophysiology, and generating sufficient statistical power and data reproducibility across laboratories. A brainstorming session yielded a number of suggestions, including calls to (a) facilitate the replication of results by standardizing protocols and samples used across laboratories; (b) improve technology by generating cheaper/faster targeting methods, reporters, and assays; and (c) improve resource sharing and collaboration, with an emphasis on rapid sharing of new cell lines, technologies, and best practices, possibly incorporated into a public-private partnership. The meeting provided an important venue for academic, government, and private sector scientists to address potential opportunities for translational and clinical applications of reprogrammed cell research. A number of activities since the workshop have reflected the feedback from meeting participants. PMID: 23408104 [PubMed - indexed for MEDLINE] Read more...
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Cortical interneurons from human pluripotent stem cells: prospects for neurological and psychiatric disease. Related Articles Cortical interneurons from human pluripotent stem cells: prospects for neurological and psychiatric disease. Front Cell Neurosci. 2013;7:10 Authors: Arber C, Li M Abstract Cortical interneurons represent 20% of the cells in the cortex. These cells are local inhibitory neurons whose function is to modulate the firing activities of the excitatory projection neurons. Cortical interneuron dysfunction is believed to lead to runaway excitation underlying (or implicated in) seizure-based diseases, such as epilepsy, autism, and schizophrenia. The complex development of this cell type and the intricacies involved in defining the relative subtypes are being increasingly well defined. This has led to exciting experimental cell therapy in model organisms, whereby fetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. On the other hand, cortical neurons generated from patient iPSCs serve as a valuable tool to explore genetic influences of interneuron development and function. This is a fundamental step in enhancing our understanding of the molecular basis of neuropsychiatric illnesses and the development of targeted treatments. Protocols are currently being developed for inducing cortical interneuron subtypes from mouse and human pluripotent stem cells. This review sets out to summarize the progress made in cortical interneuron development, fetal tissue transplantation and the recent advance in stem cell differentiation toward interneurons. PMID: 23493959 [PubMed] Read more... Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models. Related Articles Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models. PLoS One. 2013;8(3):e59685 Authors: Zeng L, Zhang P, Shi L, Yamamoto V, Lu W, Wang K Abstract Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) as models to investigate the functional impacts of NRXN1 knockdown. We first generated hiPSCs from skin fibroblasts and differentiated them into neural stem cells (NSCs). We reduced NRXN1 expression in NSCs via a controlled shRNAmir-based knockdown system during differentiation, and monitored the transcriptome alteration by RNA-Seq and quantitative PCR at several time points. Interestingly, half reduction of NRXN1 expression resulted in changes of expression levels for the cell adhesion pathway (20 genes, P=2.810(-6)) and neuron differentiation pathway (13 genes, P=2.110(-4)), implicating that single-gene perturbation can impact biological networks important for neurodevelopment. Furthermore, astrocyte marker GFAP was significantly reduced in a time dependent manner that correlated with NRXN1 reduction. This observation was reproduced in both hiPSCs and hESCs. In summary, based on in vitro models, NRXN1 deletions impact several biological processes during neurodevelopment, including synaptic adhesion and neuron differentiation. Our study highlights the utility of stem cell models in understanding the functional roles of copy number variations (CNVs) in conferring susceptibility to neurodevelopmental diseases. PMID: 23536886 [PubMed - in process] Read more... Ataxin1L is a regulator of HSC function highlighting the utility of cross-tissue comparisons for gene discovery. Related Articles Ataxin1L is a regulator of HSC function highlighting the utility of cross-tissue comparisons for gene discovery. PLoS Genet. 2013 Mar;9(3):e1003359 Authors: Kahle JJ, Souroullas GP, Yu P, Zohren F, Lee Y, Shaw CA, Zoghbi HY, Goodell MA Abstract Hematopoietic stem cells (HSCs) are rare quiescent cells that continuously replenish the cellular components of the peripheral blood. Observing that the ataxia-associated gene Ataxin-1-like (Atxn1L) was highly expressed in HSCs, we examined its role in HSC function through in vitro and in vivo assays. Mice lacking Atxn1L had greater numbers of HSCs that regenerated the blood more quickly than their wild-type counterparts. Molecular analyses indicated Atxn1L null HSCs had gene expression changes that regulate a program consistent with their higher level of proliferation, suggesting that Atxn1L is a novel regulator of HSC quiescence. To determine if additional brain-associated genes were candidates for hematologic regulation, we examined genes encoding proteins from autism- and ataxia-associated protein-protein interaction networks for their representation in hematopoietic cell populations. The interactomes were found to be highly enriched for proteins encoded by genes specifically expressed in HSCs relative to their differentiated progeny. Our data suggest a heretofore unappreciated similarity between regulatory modules in the brain and HSCs, offering a new strategy for novel gene discovery in both systems. PMID: 23555280 [PubMed - indexed for MEDLINE] Read more...
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Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Related Articles Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell. 2013 May 2;12(5):559-72 Authors: Maroof AM, Keros S, Tyson JA, Ying SW, Ganat YM, Merkle FT, Liu B, Goulburn A, Stanley EG, Elefanty AG, Widmer HR, Eggan K, Goldstein PA, Anderson SA, Studer L Abstract Human pluripotent stem cells are a powerful tool for modeling brain development and disease. The human cortex is composed of two major neuronal populations: projection neurons and local interneurons. Cortical interneurons comprise a diverse class of cell types expressing the neurotransmitter GABA. Dysfunction of cortical interneurons has been implicated in neuropsychiatric diseases, including schizophrenia, autism, and epilepsy. Here, we demonstrate the highly efficient derivation of human cortical interneurons in an NKX2.1::GFP human embryonic stem cell reporter line. Manipulating the timing of SHH activation yields three distinct GFP+ populations with specific transcriptional profiles, neurotransmitter phenotypes, and migratory behaviors. Further differentiation in a murine cortical environment yields parvalbumin- and somatostatin-expressing neurons that exhibit synaptic inputs and electrophysiological properties of cortical interneurons. Our study defines the signals sufficient for modeling human ventral forebrain development in vitro and lays the foundation for studying cortical interneuron involvement in human disease pathology. PMID: 23642365 [PubMed - in process] Read more... Bioengineered stem cells in neural development and neurodegeneration research. Related Articles Bioengineered stem cells in neural development and neurodegeneration research. Ageing Res Rev. 2013 Jun;12(3):739-48 Authors: Yuan SH, Shaner M Abstract The recent discovery of a simple method for making induced pluripotent stem cells (iPSC) from human somatic cells was a major scientific advancement that opened the way for many promising new developments in the study of developmental and degenerative diseases. iPSC have already been used to model many different types of neurological diseases, including autism, schizophrenia, Alzheimer's disease and Parkinson's disease. Because of their pluripotent property, iPSC offer the possibility of modeling human development in vitro. Their differentiation seems to follow the developmental timeline and obeys environmental cues. Clinically relevant phenotypes of neurodegenerative pathologies have also been observed using iPSC derived human neuronal cultures. Options for treatment are still some way off. Although some early research in mouse models has been encouraging, major obstacles remain for neural stem cell (NSC) transplantation therapy. However, iPSC now offer the prospect of an unlimited amount of human neurons or astrocytes for drug testing. The aim of this review is to summarize the recent progress in modeling neural development and neurological diseases using iPSC and to describe their applications for aging research and personalized medicine. PMID: 23651546 [PubMed - in process] Read more... Enhanced derivation of mouse ESC-derived cortical interneurons by expression of Nkx2.1. Related Articles Enhanced derivation of mouse ESC-derived cortical interneurons by expression of Nkx2.1. Stem Cell Res. 2013 Jul;11(1):647-56 Authors: Petros TJ, Maurer CW, Anderson SA Abstract Forebrain GABAergic interneurons are divided into subgroups based on their neurochemical markers, connectivity and physiological properties. Abnormal interneuron function is implicated in the pathobiology of neurological disorders such as schizophrenia, autism, and epilepsy. Studies on interneuron development and their role in disease would benefit from an efficient mechanism for the production and selection of specific interneuron subgroups. In this study, we engineered a mouse embryonic stem cell (mESC) line for doxycycline-inducible expression of Nkx2.1, a required transcription factor for cortical interneurons derived from the medial ganglionic eminence (MGE). This mESC line was modified to express GFP in Lhx6(+) cells, a marker of newly postmitotic and mature MGE-derived cortical interneurons. The addition of doxycycline to differentiating ESCs efficiently induced Nkx2.1 protein and increased the production of GFP(+) cells. Transplantation of GFP(+) putative interneuron precursors resulted in migratory, morphological, and neurochemical features consistent with cortical interneuron fates. To test the hypothesis that Sonic hedgehog (Shh) primarily influences cortical interneuron fate determination through the induction of Nkx2.1, ESCs were grown with doxycycline and the Shh antagonist cyclopamine. We found induced Nkx2.1 renders Shh signaling dispensable for the generation of MGE-derived interneurons. These results demonstrate that inducible expression of fate determining genes in embryonic stem cells can be used to study fate determination of the developing forebrain. PMID: 23672829 [PubMed in process] Read more... The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells. Related Articles The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells. Hum Mol Genet. 2013 Sep 15;22(18):3749-60 Authors: Shi L, Chang X, Zhang P, Coba MP, Lu W, Wang K Abstract Genetic
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mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and wholegenome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases. PMID: 23710042 [PubMed in process] Read more... Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models. Related Articles Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models. Dis Model Mech. 2013 Jul 4; Authors: Magri L, Cominelli M, Cambiaghi M, Cursi M, Leocani L, Minicucci F, Poliani PL, Galli R Abstract Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, TSC1 or TSC2. Most affected individuals display severe neurological manifestations - such as intractable epilepsy, mental retardation and autism - that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotypephenotype correlation in individuals bearing mutations in either TSC1 or TSC2 is highly controversial. Similar to observations in humans, mouse modeling has suggested that a more severe phenotype is associated with mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of either gene was achieved in differentiated astrocytes. Here, we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances and spontaneous epilepsy that have been detected in RGC-targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as STAT3-dependent and -independent developmental-stage-specific defects in the differentiation potential of ex-vivoderived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development. PMID: 23744272 [PubMed - as supplied by publisher] Read more... Therapeutic translation of iPSCs for treating neurological disease. Related Articles Therapeutic translation of iPSCs for treating neurological disease. Cell Stem Cell. 2013 Jun 6;12(6):678-88 Authors: Yu DX, Marchetto MC, Gage FH Abstract Somatic cellular reprogramming is a fast-paced and evolving field that is changing the way scientists approach neurological diseases. For the first time in the history of neuroscience, it is feasible to study the behavior of live neurons from patients with neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and neuropsychiatric diseases, such as autism and schizophrenia. In this Perspective, we will discuss reprogramming technology in the context of its potential use for modeling and treating neurological and psychiatric diseases and will highlight areas of caution and opportunities for improvement. PMID: 23746977 [PubMed - in process] Read more... MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. Related Articles MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. PLoS One. 2013;8(6):e65069 Authors: Larimore J, Ryder PV, Kim KY, Ambrose LA, Chapleau C, Calfa G, Gross C, Bassell GJ, Pozzo-Miller L, Smith Y, Talbot K, Park IH, Faundez V Abstract Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms
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between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD. PMID: 23750231 [PubMed - in process] Read more... Therapeutic role of hematopoietic stem cells in autism spectrum disorder-related inflammation. Related Articles Therapeutic role of hematopoietic stem cells in autism spectrum disorder-related inflammation. Front Immunol. 2013;4:140 Authors: Siniscalco D, Bradstreet JJ, Antonucci N Abstract Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive - stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders. PMID: 23772227 [PubMed] Read more... Stem Cells as a Good Tool to Investigate Dysregulated Biological Systems in Autism Spectrum Disorders. Related Articles Stem Cells as a Good Tool to Investigate Dysregulated Biological Systems in Autism Spectrum Disorders. Autism Res. 2013 Jun 25; Authors: Griesi-Oliveira K, Sunaga DY, Alvizi L, Vadasz E, Passos-Bueno MR Abstract Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n=7) and control samples (n=6). Nearly half of the 683 identified DEGs are expressed in the brain (P=0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD. Autism Res 2013, : -. 2013 International Society for Autism Research, Wiley Periodicals,
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Inc. PMID: 23801657 [PubMed - as supplied by publisher] Read more... Functional genomic screen of human stem cell differentiation reveals pathways involved in neurodevelopment and neurodegeneration. Related Articles Functional genomic screen of human stem cell differentiation reveals pathways involved in neurodevelopment and neurodegeneration. Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12361-6 Authors: Zhang Y, Schulz VP, Reed BD, Wang Z, Pan X, Mariani J, Euskirchen G, Snyder MP, Vaccarino FM, Ivanova N, Weissman SM, Szekely AM Abstract Human embryonic stem cells (hESCs) can be induced and differentiated to form a relatively homogeneous population of neuronal precursors in vitro. We have used this system to screen for genes necessary for neural lineage development by using a pooled human short hairpin RNA (shRNA) library screen and massively parallel sequencing. We confirmed known genes and identified several unpredicted genes with interrelated functions that were specifically required for the formation or survival of neuronal progenitor cells without interfering with the self-renewal capacity of undifferentiated hESCs. Among these are several genes that have been implicated in various neurodevelopmental disorders (i.e., brain malformations, mental retardation, and autism). Unexpectedly, a set of genes mutated in late-onset neurodegenerative disorders and with roles in the formation of RNA granules were also found to interfere with neuronal progenitor cell formation, suggesting their functional relevance in early neurogenesis. This study advances the feasibility and utility of using pooled shRNA libraries in combination with next-generation sequencing for a high-throughput, unbiased functional genomic screen. Our approach can also be used with patient-specific humaninduced pluripotent stem cell-derived neural models to obtain unparalleled insights into developmental and degenerative processes in neurological or neuropsychiatric disorders with monogenic or complex inheritance. PMID: 23836664 [PubMed - in process] Read more... The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders. Related Articles The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders. Psychopharmacology (Berl). 2013 Jul 10; Authors: Cocks G, Curran S, Gami P, Uwanogho D, Jeffries AR, Kathuria A, Lucchesi W, Wood V, Dixon R, Ogilvie C, Steckler T, Price J Abstract Until now, models of psychiatric diseases have typically been animal models. Whether they were to be used to further understand the pathophysiology of the disorder, or as drug discovery tools, animal models have been the choice of preference in mimicking psychiatric disorders in an experimental setting. While there have been cellular models, they have generally been lacking in validity. This situation is changing with the advent of patient-specific induced pluripotent stem cells (iPSCs). In this article, we give a methodological evaluation of the current state of the iPS technology with reference to our own work in generating patient-specific iPSCs for the study of autistic spectrum disorder (ASD). In addition, we will give a broader perspective on the validity of this technology and to what extent it can be expected to complement animal models of ASD in the coming years. PMID: 23839283 [PubMed - as supplied by publisher] Read more... GFAP expression and social deficits in transgenic mice overexpressing human sAPP. Related Articles GFAP expression and social deficits in transgenic mice overexpressing human sAPP. Glia. 2013 Sep;61(9):1556-69 Authors: Bailey AR, Hou H, Song M, Obregon DF, Portis S, Barger S, Shytle D, Stock S, Mori T, Sanberg PG, Murphy T, Tan J Abstract Autistic individuals display impaired social interactions and language, and restricted, stereotyped behaviors. Elevated levels of secreted amyloid precursor protein-alpha (sAPP), the product of -secretase cleavage of APP, are found in the plasma of some individuals with autism. The sAPP protein is neurotrophic and neuroprotective and recently showed a correlation to glial differentiation in human neural stem cells (NSCs) via the IL-6 pathway. Considering evidence of gliosis in postmortem autistic brains, we hypothesized that subsets of patients with autism would exhibit elevations in CNS sAPP and mice generated to mimic this observation would display markers suggestive of gliosis and autism-like behavior. Elevations in sAPP levels were observed in brains of autistic patients compared to controls. Transgenic mice engineered to overexpress human sAPP (TgsAPP mice) displayed hypoactivity, impaired sociability, increased brain glial fibrillary acidic protein (GFAP) expression, and altered Notch1 and IL-6 levels. NSCs isolated from TgsAPP mice, and those derived from wild-type mice treated with sAPP, displayed suppressed -tubulin III and elevated GFAP expression. These results suggest that elevations in brain sAPP levels are observed in subsets of individuals with autism and TgsAPP mice display signs suggestive of gliosis and behavioral impairment. PMID: 23840007 [PubMed - in process] Read more...
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Focal malformations of cortical development: New vistas for molecular pathogenesis. Related Articles Focal malformations of cortical development: New vistas for molecular pathogenesis. Neuroscience. 2013 Jul 25; Authors: Lim KC, Crino PB Abstract Focal malformations of cortical development (FMCD) are highly associated with several neurological disorders including intractable epilepsy and neurocognitive disabilities. Over the past decade, several FMCD subtypes have been linked to hyperactivation of the mammalian target of rapamycin (mTOR) signaling cascade. In view of the roles that mTOR plays in cell proliferation, size, motility, and stem cell phenotype, many of the features of FMCD such as cytomegaly, disorganized lamination, and expression of stem cell markers can be explained by enhanced mTOR signaling. FMCD result from several distinct and fascinating molecular mechanisms including biallelic gene inactivation, somatic mutation, and potentially, viral infection. These mechanisms have been directly linked to mTOR activation. Perhaps most compelling, pharmacological inhibition of mTOR has been implemented successfully in clinical trials for select FMCD and provides a new vista for treatment. PMID: 23892008 [PubMed - as supplied by publisher] Read more... Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening. Related Articles Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening. Transl Psychiatry. 2013;3:e294 Authors: Boissart C, Poulet A, Georges P, Darville H, Julita E, Delorme R, Bourgeron T, Peschanski M, Benchoua A Abstract Cortical neurons of the superficial layers (II-IV) represent a pivotal neuronal population involved in the higher cognitive functions of the human and are particularly affected by psychiatric diseases with developmental manifestations such as schizophrenia and autism. Differentiation protocols of human pluripotent stem cells (PSC) into cortical neurons have been achieved, opening the way to in vitro modeling of neuropsychiatric diseases. However, these protocols commonly result in the asynchronous production of neurons typical for the different layers of the cortex within an extended period of culture, thus precluding the analysis of specific subtypes of neurons in a standardized manner. Addressing this issue, we have successfully captured a stable population of self-renewing late cortical progenitors (LCPs) that synchronously and massively differentiate into glutamatergic cortical neurons of the upper layers. The short time course of differentiation into neurons of these progenitors has made them amenable to high-throughput assays. This has allowed us to analyze the capability of LCPs at differentiating into post mitotic neurons as well as extending and branching neurites in response to a collection of selected bioactive molecules. LCPs and cortical neurons of the upper layers were successfully produced from patient-derived-induced PSC, indicating that this system enables functional studies of individual-specific cortical neurons ex vivo for disease modeling and therapeutic purposes. PMID: 23962924 [PubMed - in process] Read more... Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Related Articles Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013 Aug 27;11(1):196 Authors: Lv YT, Zhang Y, Liu M, Qiuwaxi JN, Ashwood P, Cho SC, Huan Y, Ge RC, Chen XW, Wang ZJ, Kim BJ, Hu X Abstract BACKGROUND: Autism is a pervasive neurodevelopmental disorder. At present there are no defined mechanisms of pathogenesis and therapy is mostly limited to behavioral interventions. Stem cell transplantation may offer a unique treatment strategy for autism due to immune and neural dysregulation observed in this disease. This non-randomized, open-label, single center phase I/II trial investigated the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism. METHODS: 37 subjects diagnosed with autism were enrolled into this study and divided into three groups: CBMNC group (14 subjects, received CBMNC transplantation and rehabilitation therapy), Combination group (9 subjects, received both CBMNC and UCMSC transplantation and rehabilitation therapy), and Control group (14 subjects, received only rehabilitation therapy). Transplantations included four stem cell infusions through intravenous and intrathecal injections once a week. Treatment safety was evaluated with laboratory examinations and clinical assessment of adverse effects. The Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) were adopted to assess the therapeutic efficacy at baseline (pre-treatment) and following treatment. RESULTS: There were no significant safety issues related to the treatment and no observed severe adverse effects. Statistically significant differences were shown on CARS, ABC scores and CGI evaluation in the two treatment groups compared to the control at 24 weeks post-treatment (p < 0.05). CONCLUSIONS: Transplantation of CBMNCs demonstrated efficacy compared to the control group; however, the combination of CBMNCs and UCMSCs showed larger therapeutic effects
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than the CBMNC transplantation alone. There were no safety issues noted during infusion and the whole monitoring period.Trial registration: ClinicalTrials.gov: NCT01343511, Title "Safety and Efficacy of Stem Cell Therapy in Patients with Autism". PMID: 23978163 [PubMed - as supplied by publisher] Read more...
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Stem Cell Treatment Autism - ASCI - Asian Stem Cell Institute

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Stem Cell Treatments for Autism are currently available at ASCI