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Introduction
Long-term synaptic plasticity, the sustained synaptic modification after brief periods of repetitive synaptic activity, was
first discovered in the hippocampus[1]. This phenomenon has since been the subject of intense investigation because it was
immediately recognized as an experimental model for understanding human cognitive behavior, learning, and
memory[2,3]. Although many types of synaptic plasticity have been described,
N-methyl-D-aspartate (NMDA)-sensitive glutamate (Glu)
receptor (R)-dependent forms of synaptic plasticity in the hippocampal CA1 region remain the most extensively studied.
Over the past three decades, significant progress has been made in understanding the cellular and molecular mechanisms
underlying these forms of synaptic
plasticity[4_9]. Here, we attempt to highlight the progress with emphasis on the last ten
years.
Cellular and synaptic mechanisms
The initial studies on synaptic plasticity focused on its cellular
mechanisms[2]. These studies revealed that the activation
of NMDA-Rs and an influx of calcium ions through the receptor channels are two key processes that trigger synaptic
plasticity[2,3]. The activation of NMDA-Rs requires both depolarization and glutamate binding, which explains the two basic
properties of synaptic plasticity: input-specificity and
input-associativity. Input-specificity means that only
synapses activated by repetitive activation can be modified,
whereas other synapses on the same cell are normally not
modified. This is due to the requirement of glutamate
binding for the activation of NMDA-Rs. Input-associativity
means that neighboring even weakly-activated synapses can
be modified if co-activated with other synapses because the
summated depolarization meets the threshold for opening
NMDA-Rs.
After resolving the basic cellular mechanisms for
synaptic plasticity, much work has been directed to understanding
whether the modification occurs on the pre- or postsynaptic
sites of synapses, generating a vigorous, highly visible
debate for over a decade[3]. The most convincing evidence
lands on the postsynaptic side of
synapses[10]. However, the discovery of silent synapses and the activation of silent
synapses by long term potentiation (LTP) by Malinow and
colleagues[11], and later confirmed by many other
laboratories[12_17], largely ends the debate. These studies indicate
that synaptic plasticity can change the amount of silent
synapses, suggesting a simple postsynaptic model that
unifies many of the previously conflicting observations.
Synaptic AMPA-R trafficking
The silent synapse theory suggests synaptic trafficking
of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA)-sensitive GluRs as a promising mechanism for
synaptic modification of transmission efficacy. AMPA-Rs are
tetrameric proteins[18,19], which are composed of GluR1, GluR2,
GluR2L, GluR3, GluR4, or GluR4c, 6 subunits that are coded
by 4 genes, GluR1_4[20_22]. The imaging of green fluorescent
protein (GFP)-tagged recombinant GluR1 receptors with
2-photon microscopy has provided the first evidence that
AMPA-Rs move into dendritic spines, synaptic sites,
during synaptic potentiation[23]. Subsequent studies have
revealed that the cytoplasmic carboxyl termini of the
constituent subunits, which can be either long or short, govern
the synaptic trafficking characteristics of
AMPA-Rs[7,24]. So far, multiple distinct synaptic AMPA-R trafficking events
have been characterized (Figure 1).
AMPA-Rs with long cytoplasmic termini (ie GluR1-,
GluR2L- or GluR4-containing AMPA-Rs) are normally
restricted from synapses (Figure 1). During synaptic
potentiation (eg long-term potentiation or LTP), synaptic activity
activates NMDA-Rs and drives GluR1-, GluR2L-, or
GluR4-containing AMPA-Rs into
synapses[25_27]. The synaptic delivery of GluR1- and GluR2L-containing AMPA-Rs can be a
rapid process, taking approximately 15_25 min during
LTP[27,28]. During LTP, GluR1-containing AMPA-Rs are transported to
the plasma membrane via exocytosis from recycling
endosomes[29]. In hippocampal CA1 neurons, GluR4 is
expressed only in the first postnatal
week[25]. Spontaneous activity delivers GluR4-containing AMPA-Rs into synapses,
which mediates synaptic potentiation during early
development[25,30]. The expression of GluR2L peaks at the end of the
second postnatal week and declines by half in
adults[27]. The synaptic delivery of GluR2L-containing AMPA-Rs
requires spontaneous activity[27]. GluR1 expression increases
with increasing age and reaches a maximal expression level
after the third postnatal week[25]. Strong synaptic activity,
such as LTP-inducing stimuli, is required to drive
GluR1-containing AMPA-Rs into
synapses[26,31]. In the intact brain, experience-independent, spontaneous activity is sufficient
to drive GluR2L- and GluR4-containing AMPA-Rs into
synapses, whereas experience-dependent activity and/or the
presence of other neuromodulatory physiological factors (eg
neuromodulators, hormones, and neurotrophic factors) are
required for the synaptic delivery of GluR1-containing
AMPA-Rs[32_34]. An intriguing hypothesis for how
transmission efficacy is maintained despite continuous AMPA-R
trafficking and protein turnover involves the simultaneous
delivery of slot proteins or slot protein complexes
containing AMPA-Rs with long cytoplasmic termini during
synaptic potentiation[35]. A recent study has provided evidence
supporting the existence of slot proteins and the idea that
the hypothesized slot proteins code synaptic transmission
strength[36].
Within a short window (approximately 0.5_2 h) after
synaptic potentiation, some of the newly-delivered AMPA-Rs
with long cytoplasmic termini can be removed from synapses
(Figure 1). This process requires synaptic activity and the
activation of NMDA-Rs, and mediates
depotentiation[37]. The synaptic removal of GluR2L- and GluR1-containing
AMPA-Rs occurs rapidly and the process takes approximately
15_25 min[37]. Most likely, the slot proteins are removed
together with AMPA-Rs with long cytoplasmic termini in
order to reduce transmission
efficacy[36].
Other synaptic AMPA-Rs with long cytoplasmic termini
(ie those not removed by depotentiation) are eventually
exchanged with AMPA-Rs with only short cytoplasmic termini
(Figure 1). The synaptic exchange of GluR1-, GluR2L-, and
GluR4-containing AMPA-Rs with GluR2-containing AMPA-Rs
(ie GluR2/3 AMPA-Rs) requires no synaptic
activity[25,27,36]. This process has a slow rate time constant of approximately 16 h
and is essential for maintaining the capacity for bidirectional
plasticity[36]. The slot proteins play a key role in maintaining
transmission strength during this slow
exchange[36].
AMPA-Rs with only short cytoplasmic termini,
constitutively cycle between synaptic and non-synaptic sites (Figure
1). The synaptic cycling of GluR2-containing AMPA-Rs (ie
GluR2/3 AMPA-Rs) has a rapid time rate(time constant of
approximately 15_20 min) and the process requires no
synaptic activity[38_42]. Recent studies suggest that most of the
cycling GluR2-containing AMPA-Rs may bind to slot
proteins at the synaptic site, and the pool of cycling
GluR2-containing AMPA-Rs at the non-synaptic site is most likely
very small[36,43]. Together, synaptic AMPA-R exchange and
cycling serve to maintain synaptic strength despite
continuous protein turnover.
AMPA-Rs with only short cytoplasmic termini can be
removed from synapses (Figure 1). During synaptic
depression [eg long-term depression (LTD)], synaptic activity
activates NMDA-Rs and removes GluR2-containing AMPA-Rs
(ie GluR2/3 AMPA-Rs)[28,44_46]. The synaptic removal of
GluR2-containing AMPA-Rs can be a rapid process, taking
approximately 15_25 min during LTD[28], and the receptors
are diverted to the late endosomes/lysosomes via
clathrin-dependent endocytosis[47_50]. The slot proteins are most likely
removed together with GluR2-containing AMPA-Rs, which
accounts for the reduced transmission efficacy after
LTD[36].
GluR2-lacking AMPA-Rs may also traffic into synapses
in physiological and pathological
conditions[51]. Although the endoplasmic reticulum (ER) normally only allows
properly assembled AMPA-Rs to exit, and the majority of
AMPA-Rs that exit from the ER contain GluR2
subunits[19], some endogenous GluR2-lacking AMPA-Rs do egress from the
ER and travel into synapses[25,52,53]. For example, during early
postnatal development, the expression of GluR2 is relatively
low[25,27], and GluR2-lacking AMPA-Rs may mediate a
significant portion of synaptic
transmission[25,54]. In juvenile and adult neurons, the synaptic presence of GluR2-lacking
AMPA-Rs is regulated by the synaptic trafficking of
GluR2-containing AMPA-Rs, which are controlled by an
interaction with protein kinase C (PKC)-interacting protein 1 (PICK1)
or glutamate receptor-interacting protein (GRIP1, also called
AMPA-binding protein)[55,56]. In the normal condition, the
number of GluR2-lacking AMPA-Rs at synapses is limited
due to synaptic exchange and replacement by
GluR2-containing AMPA-Rs[36,53,57,58]. Because GluR2-lacking
AMPA-Rs are permeable to calcium, their synaptic presence is often
associated with pathological conditions, such as brain
ischemia and amyotrophic lateral
sclerosis[59_61].
Synaptic Ras/MAPK signaling
The heavy, regulated trafficking of AMPA-Rs at
synapses implicates the existence of a trafficking control
system. Ras family small GTPase_mitogen-activated
protein kinase (MAPK) signaling pathways are ideal candidates
for signaling synaptic AMPA-R trafficking events for
several reasons. First, these signaling pathways are known to
control a variety of intracellular
processes[62_64]. In addition, Ras family small GTPases Ras, Rap1, and Rap2, as well as
their upstream regulators and downstream effectors,
including p42/44 MAPK, phosphoinositide 3 kinase (PI3K), c-Jun
amino-terminal kinase (JNK), and p38 MAPK, are expressed
at synapses[6,9,65]. Finally, diseases causing cognitive
impairment are associated with genetic defects of molecules
involved in Ras-MAPK signaling (eg calcineurin with
schizophrenia[66], H-Ras with
autism[67], p38 MAPK, and JNK with Alzheimer's
disease[68,69], B-Raf with cardio-facio-cutaneous
(CFC) syndrome[70], RasGap neurofibromin with
neurofibromatosis type 1 (NF1)[71,72], tuberin with tuberous
sclerosis[73], and Rsk with Coffin-Lowry syndrome and X-linked mental
retardation[74,75]. In support of this notion, recent findings
have shown that different Ras-MAPK signaling pathways
differentially control synaptic trafficking of AMPA-Rs
during distinct forms of synaptic plasticity.
During LTP, the activation of NMDA-Rs stimulates small
GTPase Ras-extracellular signal-regulated kinase kinase
(MEK), extracellular signal-regulated kinase (ERK, also named
p42/44 MAPK), PI3K, and protein kinase B (PKB, also called
Akt) signaling pathways (Figure
2)[28,34,76]. Different signaling molecules relay the activation of NMDA-Rs to Ras at
different developmental stages, whereas neonatal neurons
require cyclic AMP-dependent protein kinase A (PKA) and
Ras activator son of sevenless and juvenile and adult
neurons need calcium/calmodulin-dependent protein kinase II
and Ras activator Ras-guanyl-nucleotide releasing factor
(GRF)[25,77,78]. The activation of the Ras-MEK-ERK pathway
stimulates phosphorylation of S841 of GluR2L and S845 of
GluR1, whereas the activation of the Ras-PI3K-PKB
pathway stimulates phosphorylation of S831 of
GluR1[34]. S841 phosphorylation of GluR2L is sufficient to drive
GluR2L-containing AMPA-Rs into synapses, while phosphorylation
of both S845 and S831 of GluR1 is required for the synaptic
delivery of GluR1-containing
AMPA-Rs[34]. Because ERK and PKB are unlikely to directly phosphorylate GluR1 and
GluR2L, other molecules must exist at synapses to relay the
signaling[63,64]. The likely candidates include
PKA[79],
PKC[80,81], ribosomal S6
kinase[74,75,82], and the mammalian target of
rapamycin[83,84]. Determining the precise functional
relationships (ie sequential or parallel, and downstream or
upstream) of the signaling molecules involved in Ras
pathways during LTP will be central to future
studies[6].
During depotentiation, the activation of NMDA-Rs
stimulates the small GTPase Rap2-Traf2 and NCK-interacting
kinase (TNIK)-JNK signaling pathway (Figure
3)[37]. The activation of the Rap2-TNIK-JNK pathway dephosphorylates
S841 of GluR2L, and S845 and S831 of GluR1, which removes
GluR2L- and GluR1-containing AMPA-Rs from synapses
during depotentiation[37]. Dephosphorylation seems to be
mediated by protein phosphatase 2B (also named calcineurin)
downstream of Rap2-TNIK-JNK[37], which is consistent with
the finding that calcineurin mediates
depotentiation[85_87].
During LTD, the activation of NMDA-R stimulates the
small GTPase Rap1-p38 MAPK signaling pathway (Figure
4)[28]. Phosphorylation of S880 of GluR2 modulates the
interaction of GluR2 with GRIP1 and
PICK1[46,88,89], which
controls the synaptic anchoring of GluR2-containing
AMPA-Rs[90_96]. Thus, the activation of the Rap1-p38 MAPK
pathway most likely controls the synaptic removal of
GluR2-containing AMPA-Rs during LTD via regulating
phosphorylation of S880 of
GluR2[28,44,46]. Because p38 MAPK does not
phosphorylate AMPA-Rs directly[63,97], other synaptic
signaling molecule(s), such as
PKC[88,89,92] and/or MAPK-interacting
kinase[98], may relay the signaling and phosphorylate
GluR2.
Conclusion
In the last decade, accumulating evidence indicates that
postsynaptic trafficking of AMPA-Rs plays a key role in
regulating synaptic transmission and plasticity. Multiple
Ras-MAPK signaling pathways control the regulated
synaptic trafficking of AMPA-Rs during different forms of
synaptic plasticity. However, a few fundamental issues remain
unsolved, for example, different populations of synapses in
individual neurons having distinct AMPA-R compositions.
How AMPA-Rs recognize and traffic into different types of
synapses remains puzzling. Also, many of the regulators in
Ras-MAPK signaling pathways have poor selectivity in
interacting with their effectors. How different Ras-MAPK
pathways differentially signal trafficking of distinct pools of
AMPA-Rs at single synapses is still elusive. More
impor-tantly, how synaptic AMPA-R trafficking and Ras-MAPK
signaling are regulated in different behavioral states in the
intact brain remains largely unknown. One speculation is
that AMPA-R trafficking and Ras-MAPK signaling are
compartmentalized between and within synapses, and
compartmentalized trafficking and signaling are differentially
regulated in different behavioral states. Resolving the
subcellular compartmental protein trafficking and signaling in these
physiological conditions demands high-resolution
experimental techniques. Several recently-refined techniques,
including multiple whole-cell in vivo
recordings[99_103], real time single spine Ras/kinase activity
monitoring[104,105], living cell imaging and immunogold electron
microscopy[106_110], when combined with a recombinant DNA
in vivo delivery
technique[32_34,36,111], provide powerful high-resolution
approaches that may resolve these pivotal issues.
Acknowledgements
We thank the members of the Zhu Laboratory for helpful
comments and discussions. In addition, we apologize to
those whose work we did not cite because of space
limita-tions.
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