BMSN3102

Autism and Schizophrenia

Dr. L. W. LIM
School of Biomedical Sciences
The University of Hong Kong
limlw@hku.hk
 Learning Objectives

Describe the synaptic dysfunction in autism.

Describe the synaptic dysfunction in schizophrenia.
Autism Spectrum Disorders (ASD)

Neurodevelopmental disorders, with key features develop in ~2-3 years old.

Comprises of heterogeneous group of conditions (DSM IV), including:
(1) Aspergers syndrome
(2) Pervasive Developmental Disorder- Not Otherwise specified (PPD-NOS).
(3) Autistic Disorder
(4) Rett syndrome
(5) Childhood disintegrative disorder

Major features:
Defective social interactions
Impaired communication
Stereotypic and repetitive behaviours
Language impairments
Epilepsy (~30% of the cases)
Savant abilities (~10% is associated with specialized
abilities, e.g. music, mathematics, memory)
Features of Autism

1. Difficulty in mixing 2. Inappropriate 3. Little or no eye 4. Apparent in activity

5. Prefer to be alone. 6. Spins objects.
with other children. laughing or giggling. contact. to pain.

7. Inappropriate 8. Noticeable physical 9. Unresponsive to 10. Insistence on 11. No real fear of

overactivity or extreme 12. Sustained odd play.
attachment to objects. normal teaching sameness; resists danger.
underactivity. methods. changes in routine.

13. Repeating words or 14. May not want 15. Not responsive to 16. Difficulty in expressing 17. Tantrum displays 18. Uneven gross fine
phrases in place of cuddling or act cuddly. verbal cues; acts as deaf. needs; uses gestures or extreme distress for no motor skills (may not want
normal language. pointing instead of words. apparent reason. to kick ball but stack
blocks).
Prevalence and NIH Funding for Autism Research

Diagnosis: rising
By some counts, autism diagnoses have climbed steadily since the 1970s. Some research has
found explanation for more than half of the rise (right).
Types of ASD
Asperger's Syndrome
The mildest form of autism or
hidden disability
affects boys three times more often
than girls.
Obsession, Impaired social skills
normal to above average intelligence,
"high-functioning autism."
high risk for anxiety and depression.
Rett Syndrome
exhibit autistic-like behaviors.
genetic mutation and unrelated to
ASD.
Primarily affecting females.
Pervasive Developmental Disorder, Not
Otherwise Specified (PDD-NOS)
applies to most children with ASD.
More severe than Asperger's syndrome, but not
as severe as autistic disorder
Autism symptoms vary widely:
Impaired social interaction,
Better language skills than kids with autistic
disorder but not as good as those with
Asperger's syndrome
Fewer repetitive behaviours than children with
Asperger's syndrome or autistic disorder
A later age of onset
Autistic Disorder
Rigid diagnosis criteria for autistic disorder.
Impairment on social Interaction and language
functioning, as well as repetitive behaviours.
They also have mental retardation & seizures.
ASD Risk Factors

Genetic factors certain genetic mutations may make a

child more likely to develop ASD.
Environmental factors during pregnancy, a child may be
exposed to certain environmental factors that could
increase the risk of developing ASD.
Psychological factors people with ASD may think in
certain ways that tend to heighten their symptoms.
Neurological factors problems with the development of
the brain and nervous system may contribute to the
symptoms of ASD.
Other health conditions.
Genetic and Environmental Factors

The distributive diagram of loci or genes

that may be correlated with autism
Parts of the Brain affected by Autism
Parts of the Brain affected by Autism
Parts of the Brain affected by Autism
Parts of the Brain affected by Autism
Neural Circuit Dysfunction in Autism

Numerous rare genetic mutations have been linked to Autism Spectrum Disorder
(ASD). Many of these converge on molecular pathways related to the regulation of
synapses and neuronal circuits, which are probably responsible for the behavioural
symptoms associated with ASD. Targeting synaptic and neural circuit dysfunction in
ASD may provide a tractable approach for development of new therapies.
Synapse Development

The PI3K/AKT/mTOR pathway

is an intracellular signaling
pathway important in
regulating the cell cycle,
related to cellular quiescence,
proliferation.

Adhesion molecules
(neuroligin/neurexin)
Scaffold proteins
(Shank, PSD-95)
PSD-95 functional
bridge interconnecting
Protein synthesis near
the NRXN-NLGN- synapse
SHANK pathway.
Synapse Development

Synaptic proteins
participate in the
formation, Proteins in which a
stabilization and mutation in their
function of the encoding genes affects
synapse. social behavior are
marked in green.
Synapse Development

The main synaptic proteins and receptors

involved in synaptogenesis and function.

Excitatory synapse Inhibitory synapses

maturation and function. formation and function
Schizophrenia

schizein (, "to split") and phrn, phren- (, -, "mind")

Onset:
late adolescence or early adulthood

Epidemiology:
1% of the general population
50% for monozygotic twins of schizophrenic persons
40% of children where both parents have the disease
Men (age 15-25; 40%) and Women (age 25-35; 23%); no gender difference.

Symptoms:
Positive (Hallucination, delusion, speech/movement disorders, & thought disorder)
Negative (Social withdrawal, apathy, emotional blunting, anhedonia)
Cognitive (Deficits in executive function, attention and working memory problem)
Five Types of Schizophrenia

Catatonic little to no movement; possibly a vegetative state; bizarre

posturing.
Disorganized disorganized thinking; inappropriate emotions or
behavior; age of onset is before 25.
Paranoid delusions; hallucinations; false beliefs of grandeur; older age
of onset.
Residual Flat affect; social withdrawal; has one schizophrenic
episode and shows negative symptoms, but no psychotic symptoms.
Undifferentiated does not fit in one of the above categories because
patient suffers from multiple symptoms (the most common type).

Hallucinations
- Hearing voices when alone in a room
- Smelling non-existent odours
- Types: Auditory, Visual, Tactile, Gustatory, Olfactory, Cenesthetic (visceral)
Famous People with Schizophrenia

John Nash Novel Prize winner

Mary Todd Lincoln wife of Abraham Lincoln

A Beautiful Mind, was created based on

the life of schizophrenic John Nash
The movie drew the audience into
Nashs delusions, with the imagined
people and conspiracies seeming to be
completely real.
Etiology
Schizophrenia
Physiologic Abnormalities
EEG: Neuroendocrinology:
Decreased alpha waves Decrease in LH and FSH
Increased theta and delta waves Abnormal regulation of cortisol
Epileptiform activity
Laboratory findings:
Eye Movement: Elevated levels of homovanilic acid
Poor extraocular muscles in 50-80% (dopamine metabolite)
of the patients.

Mimics of Schizophrenia
Psychiatric Illnesses: Medical Illnesses:
Brief psychotic disorder Temporal lobe epilepsy
Schizophreniform disorder Neurologic disease or trauma
Schizoaffective disorder Poisoning
Manic phase of bipolar Endocrine disorders
Schizotypal personality disorders
Substance abuse (amphetamines)
Schizophrenia & dendritic spine pathology

Magnetic resonance imaging (MRI):

Smaller brain volume (the frontal cortex and the temporal lobe)
Loss of Gray Matter
Post-mortem study:
Decreased in dendritic spines density in the frontal and auditory cortex.
Smaller pyramidal neurons and neuropiles in cortex
Schizophrenia Ventricular Dilatation

People with schizophrenia who are medication compliant have an

association with enlarged lateral ventricles in the brain.

BMC Psychiatry. 2013; 13: 342.

The Brain in Schizophrenia
Neuregulin 1 Gene (NRG1)
The Neurotransmission in Schizophrenia
Genetic factors associated with Schizophrenia
The Dopamine Hypothesis
The Dopamine Hypothesis
The Glutamate Hypothesis
Treatment
Pharmacological Traditional/typical (against positive symptoms)
and Atypical (against negative symptoms) antipsychotics.
Pscyhological long-term support by individual, family, and group
psychotherapy.
Classification Agent Dose (mg/day) Clinical Use
Traditional Thioridazine 200 - 600 Depression with intense anxiety / agitation
Low-potency Chlorpromazine 100 - 800 To treat nausea and vomiting, Hiccups
Psychosis secondary to organic syndrome;
Haloperidol 2 - 15
Tourette disorder
Traditional Perphenazine 8 - 40 To treat nausea and vomiting
High-potency
Pinmozide 1 - 10 Tourette disorder, body dysmorphic disorder
Trifluoperazine 4 - 20 Non-psychotic anxiety
Effective for negative, chronic, and refractory
Clozapine 300 900
symptoms
Atypical Anti-
psychotics Risperidone 48 For negative symptoms; few side effects
Olanzapine 10 -20 For negative symptoms; few side effects