587

Local protein synthesis and its role in synapse-specific plasticity

Kelsey C Martin*, Mark Barad and Eric R Kandel
Long-lasting forms of learning-related synaptic plasticity require
transcription and yet occur in a synapse-specific manner,
indicating that there are mechanisms to target the products of
gene expression to some but not other synapses of a given cell.
Studies in a variety of systems have indicated that mRNA
localization and synaptically regulated local protein synthesis
constitute one such mechanism. The cellular and molecular
mechanisms underlying RNA localization and regulated translation
in neurons are just beginning to be delineated, and appear to be
similar to those used in asymmetric non-neuronal cells.
Addresses
*Department of Psychiatry and Biobehavioral Sciences, Brain
Research Institute, and * Department of Biological Chemistry, Gonda
Center, University of California, Los Angeles, 695 Charles Young Drive
South, Los Angeles, CA 90095-1761, USA
*e-mail: kcmartin@mednet.ucla.edu
e-mail: mbarad@mednet.ucla.edu
Howard Hughes Medical Institute and Center for Neurobiology and
Behavior, New York State Psychiatric Institute, College of Physicians
and Surgeons of Columbia University, New York, NY 10032, USA;
e-mail: erk5@columbia.edu
Current Opinion in Neurobiology 2000, 10:587592
0959-4388/00/$ see front matter
2000 Elsevier Science Ltd. All rights reserved.
Abbreviations

CaMKII
Ca2+/calmodulin-dependent protein kinase II
CPE
cytoplasmic polyadenylation element
CPEB
CPE binding protein
eEF2
eukaryotic elongation factor 2
eIF4e
eukaryotic initiation factor 4e
FMRP
fragile X mental retardation protein
GFP
green fluorescent protein
LTD
long-term depression
MAP2
microtubule-associated protein 2
mGluR
metabotropic glutamate receptor
NMDA
N-methyl-D-aspartate
UTR
untranslated region

Introduction
Recent studies in a variety of cell types have provided
increasing evidence that the localization of mRNAs to
distinct subcellular compartments serves as an important
mechanism for regulating gene expression [1]. Regulated
translation of localized mRNAs decentralizes the control
of gene expression and shifts part of the control from the
nucleus to distinct subcellular compartments, allowing
the macromolecular composition of a specific compartment in a cell to be altered rapidly. This form of
decentralization may prove to be particularly important in
neurons, which are unique among cells in their extreme
functional and morphological polarity, with each of the
potentially thousands of presynaptic terminal boutons
and postsynaptic spines made by a single neuron capable
of operating as an autonomous compartment. There is
strong evidence that the ability of these synaptic terminals to change the strength of their connections with

experience is a cellular mechanism underlying learning

and memory [2,3]. Like memory, synaptic plasticity
occurs in both short- and long-lasting forms. Unlike the
short-term forms, the long-lasting forms require the synthesis of new mRNA and protein [4,5]. A number of
models have been postulated to explain how long-lasting,
transcription-dependent forms of synaptic plasticity can
occur in a synapse-specific manner [69]. According to
one model, the products of gene expression are delivered
throughout the cell, but only function to increase synaptic strength at a synapse that has been tagged, in a
protein-synthesis-independent manner, by synaptic
activity. According to a second model, synaptic stimulation alters the targeting of molecules either RNA or
protein from the cell soma to the stimulated synapse.
A third model involves the local translation of dendritically localized mRNAs. By spatially restricting gene
expression, RNA localization and regulated translation
provide a means whereby transcription-dependent
changes can rapidly occur in a synapse-specific manner.
In this review we will discuss studies demonstrating a
role for RNA localization and local protein synthesis during long-lasting forms of synaptic plasticity in neurons.
To place the studies of neurons into a larger cell-biological context, we will also discuss studies from
non-neuronal cells in which the mechanisms underlying
RNA localization and regulated translation have been
characterized, as well as studies indicating that many of
these mechanisms may be used in neuronal cells as well.

A brief history of the discovery of mRNA in

dendrites
The initial indication that translation might occur in compartments other than the cell body came from the discovery
by Steward and Levy in 1982 of synapse-associated polyribosome complexes (SPRCs): clusters of polyribosomes and
associated membranous cisterns selectively localized in distal processes beneath postsynaptic sites on the dendrites of
central nervous system (CNS) granule cell neurons [10].
SPRCs were subsequently confirmed by numerous other
investigators, giving empirical support to the idea that synaptic activity might regulate local protein synthesis. This idea
gained momentum when in situ hybridization studies
showed that, although most mRNAs in the brain were present exclusively in the cell body, a select population of
mRNAs was present in the dendritic compartment of vertebrate neurons and in the unpolarized neurites of invertebrate
neurons (for reviews, see [11,12]). The restricted number of
mRNAs present in neuronal processes suggested that this
population of mRNAs consisted of transcripts critical for
synaptic function. Finally, immunohistochemical studies (at
the light- and electron-microscopic levels) demonstrated that
many components of the translational machinery, including
initiation and elongation factors as well as organelles

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Neuronal and glial cell biology

involved in the synthesis of membrane proteins, are present

in dendrites [13,14]. Taken together, these studies indicate
that all the molecules required to synthesize new proteins
are present in distal dendrites and neurites.
It is worth noting that there also is evidence from a number of systems that mRNAs, and in some cases, ribosomes,
are localized not only to the dendritic but also to the axonal
compartment [15]. However, most of these studies come
from work on neurons that are not strictly polarized into
dendritic and axonal processes. For example, some of
these studies were performed in invertebrate neurons [16]
which are not polarized into discrete axons and dendrites
but rather contain, within a single neuritic process, both
transmissive and receptive surfaces. In other cases, the
studies were carried out on sympathetic neurons [17,18],
which also lack the strict polarity of vertebrate CNS neurons. Finally, in still other cases, the studies describe
mRNA localization and protein synthesis within axonal
growth cones of developing neurons [19,20]. These latter
studies show elegantly and convincingly that local protein
synthesis is likely to be involved not only in synaptic plasticity but also in synaptogenesis. However, in this review,
we will limit our focus specifically to the role of RNA localization and local protein synthesis during synaptic
plasticity, which appears to occur in the postsynaptic, dendritic compartment of vertebrate synapses and in the
neuritic processes of invertebrate neurons.

Local protein synthesis in neuronal processes

A number of approaches have demonstrated that dendritic
protein synthesis occurs. Biochemical and mechanical fractionation has been used to enrich samples for synaptic
compartments, and metabolic labeling experiments have
revealed that these fractions are capable of synthesizing
proteins [21,22]. A foreign mRNA was microinjected into
dissected neurites of Lymnaea neurons and found to be
translated [23]. In some studies, this extra-somatic translation was found to be regulated. For example, metabotropic
glutamate receptor agonists were found to stimulate translation in synaptoneurosomes [22]. Synaptically regulated
dendritic protein synthesis was demonstrated in 1993 by
Feig and Lipton [24] who used 3H leucine labeling and
autoradiography to show that simultaneous application of
cholinergic agonists and electrical stimulation to the
Schaeffer collateral pathway of the hippocampus produced
increases in translation in the dendritic layer without any
effect on translation in the cell body compartment.

Functions for local protein synthesis

A requirement for dendritic protein synthesis during neurotrophin-induced forms of long-term potentiation of rodent
hippocampal Schaeffer collateral synapses was demonstrated
by Kang and Schuman [25], who found that brief applications
of neurotrophins to hippocampal slices produced a long-lasting potentiation that had a very rapid dependence on protein
synthesis. This translation-dependent form of plasticity persisted even after the cell body layers of the pyramidal cells in

area CA3 and CA1 were severed from the dendritic layer,
strongly suggesting that protein synthesis occurred and was
required in the dendritic compartment.
Studies of long-lasting facilitation of Aplysia sensory-motor
neuron synapses have defined a particular role for local
protein synthesis by showing that it is required, in a compartment-specific manner, to achieve synapse-specific
forms of long-term synaptic plasticity [26,27,28].
Martin et al. [26] established a three-cell culture system in
which a single Aplysia sensory neuron with a bifurcated
process made synaptic contact with two spatially separated
motor neurons. Repeated application of the modulatory
neurotransmitter serotonin to the connections made onto
one of these motor neurons produced a long-lasting, transcription-dependent facilitation of this connection without
any change in the strength of the synapse made onto the
second motor neuron. This synapse-specific facilitation,
could, however, be captured by the second branch, if that
branch was tagged by a single pulse of serotonin, which by
itself produced only short-term facilitation. Synapse-specific long-term facilitation was found to depend on local
protein synthesis in the sensory cell process. Isolated sensory cell processes were further shown to be capable of
protein synthesis, and this protein synthesis was strongly
stimulated by application of serotonin. By comparing
synapse-specific forms of long-lasting facilitation with cellwide forms of long-lasting facilitation and with long-lasting
facilitation produced by synaptic tagging [26,27], local
protein synthesis in the distal sensory cell process was
found to be important in two discrete processes: retrograde
signaling to the nucleus to initiate transcription, and the
stabilization of new synaptic growth. In a complementary
set of experiments performed in intact, acutely dissected
ganglia, Scherff and Carew [28] described a form of longlasting plasticity of Aplysia sensory-motor synapses that
also required local protein synthesis in the distal compartment. This requirement for local protein synthesis at the
synapse occurred immediately after serotonin application,
and was followed by a delayed requirement for protein
synthesis in the cell body.
Bear and colleagues [29] have recently shown a role for
synapse-specific protein synthesis during long-term depression (LTD) of hippocampal CA3CA1 synapses. LTD
produced by bath application of metabotropic glutamate
receptor (mGluR) agonists was found to require protein but
not RNA synthesis. This protein synthesis was found to occur
in dendrites: first, it was very rapidly blocked by application
of protein-synthesis inhibitors; second, it was blocked by
injection of membrane-impermeant translational inhibitors
into the postsynaptic cell; and third, LTD could be produced
in slices in which the CA1 cell bodies had been severed from
the neuropil of the stratum radiatum. Paired-pulse low-frequency stimulation was used to produce pathway-specific
mGluR-dependent LTD. This LTD also showed a rapid
dependence on protein synthesis, indicating that mGluR activation can regulate translation in a synapse-specific manner.

Local protein synthesis and its role in synapse-specific plasticity Martin, Barad and Kandel

These findings raise a number of important questions:

what is the population of mRNAs present in dendritic
compartments, how are these mRNAs localized, and how
is their translation regulated? To date, most dendritically
localized mRNAs have been identified fortuitously in the
course of in situ hybridization studies. An unbiased characterization of the entire mRNA population in dendrites is
hindered by the difficulty of preparing pure dendritic
preparations. Tian et al. [30] have recently reported
cloning expressed sequence tags from postsynaptic density
fractions of rat hippocampus. When followed by in situ
hybridization studies to confirm dendritic localization, this
approach promises to identify novel dendritically localized
transcripts. The mechanically isolated neuronal processes
of Aplysia sensory neurons have also been used as a starting
material for generating a cDNA library. Characterization of
this library also promises to identify transcripts involved in
synapse-specific forms of plasticity [31].

How is mRNA localized to specific sites in

non-neuronal cells?
The mechanisms underlying RNA localization have been
well studied in non-neuronal cells [1,32]. In Drosophila
oocytes, localization of the morphogen bicoid to the anterior pole depends on cis-acting sequences in the
3 untranslated region (UTR), which bind to a trans-acting
protein called Staufen. Staufen-mediated localization of
bicoid involves large RNA granules that are transported
along the microtubule network. In a similar fashion, localization of the transforming growth factor Vg1 to the vegetal
pole of Xenopus oocytes depends on cis-acting sequences in
the 3UTR, which bind to a Staufen homolog called Vera,
and Vera-mediated transport of Vg1 mRNA requires the
microtubule network. 3UTR cis-acting and Staufen
homolog trans-acting factors also have been identified in
somatic cells. In fibroblasts, transport of -actin mRNA to
the leading edge is critical for motility [33]. A cis-acting
sequence in the 3UTR of -actin mRNA, termed the zip
code, is bound by a zip-code-binding protein which is
homologous to Vera, and transport to the leading edge of
the fibroblast depends on the microfilament network. In
oligodendrocytes, the mRNA-encoding myelin basic protein (MBP) is transported to the oligodendrocyte process.
This localization depends on two spatially separated
cis-acting sequences in the 3UTR of the MBP mRNA as
well as the kinesin motor and the microtubule network [34].

How is mRNA targeted to neuronal dendrites?

Similar mechanisms to those described above are beginning
to be described in neurons. Mayford et al. [35] have found
that the dendritic localization of CaMKII (Ca2+/calmodulin-dependent protein kinase II) depends on signals in
the 3UTR. When fused to -galactoside mRNA, the
3UTR of CaMKII is sufficient to mediate dendritic localization of this mRNA. Miller and Mayford [36] have
recently introduced a CaMKII transgene lacking the
3UTR into CaMKII-null mice. These mice completely
lack dendritically localized CaMKII mRNA and will thus

589

be important tools in delineating the role of CaMKII

mRNA localization and local protein synthesis during learning and synaptic plasticity. Signals involved in dendritic
transport have also been mapped and found to be present
in the 3UTR of microtubule-associated protein 2 (MAP2)
mRNA [37]. Similarly, dendritic transport of BC1 RNA, an
RNA polymerase III transcript of unknown function, has
been found to depend on sequences in the 3UTR [38].
Transport of RNA granules, much like that observed in
Drosophila oocytes, has been observed in living neurons
and found to occur as ribonucleoprotein particles. Using
vital dyes to label RNA, Knowles, Bassell, Kosik and colleagues [39] detected RNA granules translocating into
dendrites of cultured hippocampal neurons at a rate of
approximately 6 m/min in a manner that was stimulated
by neurotrophin application [40]. In a set of studies that
provide the beginnings of a molecular understanding of
RNA transport into neuronal dendrites, Kiebler et al. [41]
found that the mammalian homolog of Staufen was
restricted to the somatodendritic compartment of mature
hippocampal neurons, where it was present in large ribonucleoprotein granules. Furthermore, transfection of green
fluorescent protein (GFP)-labeled Staufen in primary cultured hippocampal neurons revealed that, although the
majority of Staufen remained stationary in the somatic
compartment, a fraction of labeled Staufen translocated
into the dendrite in a saltatory fashion at a rate of approximately 6 m/min [42]. Consistent with the idea that
these RNA granules are being transported along microtubules, antisense suppression of the microtubule motor
protein kinesin was found to specifically alter the dendritic
localization of CaMKII mRNA in neurons [43].
Studies of the immediate early gene Arc indicate that the
dendritic translocation of mRNAs is a highly regulated
process. Arc is a cytoskeletal-associated protein of
unknown function whose RNA is expressed at very low
levels in unstimulated rodent hippocampus. After tetanic
stimulation, the mRNA for Arc is strongly induced as an
immediate early gene and is rapidly transported into the
dendrite [44,45]. The transport of Arc mRNA is spatially
regulated: stimulation of part of the perforant pathway to
activate a distinct lamina of synapses in the dentate gyrus
produces specific targeting of Arc mRNA to that lamina
[46]. This targeting appears to be dependent on cis-acting
sequences in the mRNA as it occurs in the presence of protein-synthesis inhibitors. Further indication that dendritic
mRNA targeting is regulated comes from studies by
Schacher et al. [47] showing that mRNA export into
Aplysia neurites is regulated by the postsynaptic neuron.

In neurons, targeting to dendrites can be

regulated by mechanisms that operate at both
the 3 and 5 end of the mRNA
To function as a mechanism of spatially regulating gene
expression, mRNA localization must be accompanied by
regulated translation of that mRNA. An understanding of

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Neuronal and glial cell biology

some of the molecular mechanisms underlying translational regulation of dendritically localized mRNAs is
beginning to emerge. Translation of one of the most
abundant dendritically localized mRNAs in the rodent
hippocampus, that encoding CaMKII, increases specifically in the dendritic compartment following tetanic
stimulation [48] although the extent of, and mechanism
mediating, this increase is controversial [49]. Scheetz
et al. [50] found that in the superior colliculus of young
rats, NMDA activation increased the synthesis of
CaMKII. Because NMDA activation also increased
eukaryotic elongation factor 2 (eEF2) phosphorylation,
which is known to decrease overall protein synthesis, the
authors hypothesize that activity-induced decreases in
overall translation might promote the translation of a
specific subset of mRNAs.
Mechanisms of translational regulation are often divided
into 3 and 5 mechanisms, with cytoplasmic polyadenylation being a clear example of a 3 mechanism of translational
regulation [51]. During development, many transcripts are
translationally regulated by a process called cytoplasmic
polyadenylation. These transcripts contain a particular
sequence in their 3UTR termed the cytoplasmic
polyadenylation element (CPE). Upon stimulation (e.g. fertilization of an egg), the CPE binding protein (CPEB) binds
to the CPE, recruiting the polyA polymerase resulting in an
increase in the length of the polyA tail, which in turn promotes translation of the transcript. Joel Richter, Justin
Fallon and their colleagues [52] have shown that CPEB is
present in the dendritic compartment of the hippocampus,
that the 3UTR of CaMKII contains a potential CPE, and
that when dark-reared rats are exposed to light for a 30 min
period, the length of polyA tail of CaMKII increases in the
visual cortex. These findings indicate that synaptic stimulation may regulate local translation of CaMKII through
cytoplasmic polyadenylation.
A common mechanism of 5 translational control involves
rapamycin-sensitive translation. Rapamycin is an immunosuppressant that stops the translation of a select number of
mRNAs in the cell [53]. Many of these transcripts contain
terminal oligopyrimidine tracts in their 5UTRs, and their
translation requires the modulation of eukaryotic initiation
factor 4e (eIF4e) and ribosomal protein S6 kinase. Yanow
et al. [54] have shown that intermediate-term facilitation of
Aplysia sensory-motor connections in dissected ganglia is
dependent upon rapamycin-sensitive protein synthesis.
Casadio et al. [27] found that approximately 60% of serotonin-induced translation in isolated sensory cell neurites
was rapamycin-sensitive. They further found that the
rapamycin-sensitive translation appeared to be specifically
involved in the stabilization of structural changes. Erin
Schuman and colleagues [55] have found that the known
components of the rapamycin-sensitive pathway (eIF4e,
eIF4e-binding protein [eIF4eBP], S6 kinase) are all present in the dendrites of hippocampal neurons in culture.
These data indicate that 5-mediated mechanisms are also

likely to play a role in synaptically regulated translational

control. Interestingly, recent studies from Joel Richter and
colleagues [56] have identified a molecule, maskin, that
binds to both CPEB and eIF4e, and may unify 3UTR and
5UTR (rapamycin-sensitive) mechanisms.
A role for mRNA targeting and local protein synthesis has
emerged from the studies of fragile X mental retardation
[57]. The fragile X mental retardation protein (FMRP) is
an RNA-binding protein that shuttles between the nucleus
and the cytoplasm. Its mRNA has been detected in dendritic spines, and stimulation of synaptoneurosomes with
mGluR agonists has been shown to increase FMRP translation [58]. Patients with fragile X mental retardation most
frequently do not express FMRP, and post-mortem examination of their brains reveals that they have defects in
dendritic spine structure.

Conclusions
In summary, abundant evidence indicates that local protein synthesis occurs in neurites and dendrites, that it is
essential for some forms of synaptic plasticity, and that it is
at least partially regulated by neurotransmitters. Only a
subset of mRNAs are localized to the synaptic compartments, and some additional mRNAs are transported
specifically in response to synaptic stimulation.
Localization and translational control of synaptic mRNAs
seems to depend upon mechanisms shared with other
localized mRNAs, being dependent on sequences in the
3UTR, on the microtubule network, and on trans-acting
factors such as Staufen. Translational control appears to be
exerted by both 5 and 3 mechanisms. Only a few synaptically localized mRNAs have been identified, but large
unbiased screens are in progress, as well as studies aimed
at elucidating the specific mechanisms of synaptic localization and translational control by synaptic stimulation in
neurons. Together, these studies promise to delineate a
new level in the integrative action of neurons, which differs from the classical Sherringtonian integration that
dominated our thinking in the 20th century, in both its
long time-course and its compartmental restriction.

Update
In a recent study, Christophe Schuster and colleagues
[59] provide evidence that postsynaptic translational
regulation also plays a role in long-lasting plasticity at the
neuromuscular junction, with the local translation occurring subsynaptically in the larval muscle. The authors
first show that components of the translational machinery
and polyribosomes are associated with the subsynaptic
reticulum of Drosophila larval neuromuscular junctions.
They then use a variety of genetic manipulations to show
that altering the occurrence of subsynaptic translation
aggregates also changes the levels of synaptic proteins, as
well as the morphology and function of the neuromuscular junction. Finally, they show that subsynaptic
translation appears to be regulated by altered levels of
neuronal activity.

Local protein synthesis and its role in synapse-specific plasticity Martin, Barad and Kandel

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