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Selye originally described stress as a nonspecific
response of the body to any demand placed upon it1.
Now it is customary to speak of a stressor as an event
or experience that threatens the ability of an individual
to adapt and cope2. As a result, the stressor evokes a
stress response, which involves the release of hormones
and other cellular mediators that can promote adapta-
tion when the response is efficiently turned on and shut
off, but which can also promote pathophysiological
processes when the response is overused or dysregu-
lated3. The brain is central in the adaptation to stress,
as it perceives and determines what is threatening, and
orchestrates the behavioural and physiological responses
to the stressor4. The brain is also a target of stress, with
animal models showing stress-induced remodelling of
brain architecture, such as dendritic atrophy and loss
of dendritic spines in neuronal populations5–7. The
effects of stress on the brain have long been associated with
the onset and exacerbation of several neuropsychiatric
disorders.
Depending on the age of the animal at the time of
exposure and the duration and type of stressor experi-
enced, stress also has marked and often divergent effects
on learning and memory8,9. In relation to these effects,
stress is known to influence several distinct cognitive
processes, including spatial and declarative memory
(which involves the hippocampus), the memory of
emotionally arousing experiences and fear (which
involves the amygdala), and executive functions and
fear extinction (which involves the prefrontal cortex
(PFC)). This Review focuses primarily on the PFC, as
it may have an important role in mediating the effects
of stress on both cognition and psychopathology. The
PFC is an essential component of a neural circuit for
working memory10,11, which is the ability to keep
in mind something that has just occurred or to bring to
mind events in the absence of direct stimulation. PFC
neurons show spatially tuned, persistent activity during
the delay period of working memory tasks, a phenom-
enon that is thought to arise from recurrent excitatory
connections involving AMPA receptor (AMPAR) and
NMDA receptor (NMDAR) synapses onto PFC pyrami-
dal neurons11,12. The PFC is also essential for behavioural
adaptation, as it inhibits inappropriate actions and
allows for a flexible regulation of behaviour that ena-
bles a proper response to changes in the environment.
Multiple lines of evidence from rodent and human stud-
ies also implicate the ventromedial PFC as the major site
controlling extinction of conditioned fear13,14. Moreover,
impaired PFC function and plasticity is thought to be
a core patho logical feature of several neuropsychiatric
disorders15–17. As stress seems to induce some effects in
the PFC that are unique to this region and other effects
that are common to the hippocampus and other regions,
regional comparisons will be made where possible (see
Supplementary informationS1 (table)).
For the purpose of clarity and focus, and to high-
light the importance of several recent findings, this
1Center of
Neuropharmacology,
Department of
Pharmacological Sciences
and Center of Excellence on
Neurodegenerative Diseases,
University of Milan,
20133 Milan, Italy.
2Department of Physiology
and Biophysics, School of
Medicine and Biomedical
Sciences, State University
of New York, Buffalo,
New York 14214, USA.
3Laboratory of
Neuroendocrinology, The
Rockefeller University, New
York, New York 10065, USA.
4Department of Psychiatry,
Clinical Neuroscience
Research Unit, Yale University
School of Medicine, New
Haven, Connecticut 06511,
USA.
Correspondence to G.S.
e-mail: gerard.sanacora@
yale.edu
doi:10.1038/nrn3138
Published online
30 November 2011
The stressed synapse: the impact
of stress and glucocorticoids on
glutamate transmission
Maurizio Popoli1, Zhen Yan2, Bruce S. McEwen3 and Gerard Sanacora4
Abstract | Mounting evidence suggests that acute and chronic stress, especially the
stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission
in the prefrontal cortex and the hippocampus, thereby influencing some aspects of
cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is
increasingly considered to be a core feature of stress-related mental illnesses. Recent
studies have shed light on the mechanisms by which stress and glucocorticoids affect
glutamate transmission, including effects on glutamate release, glutamate receptors
and glutamate clearance and metabolism. This new understanding provides insights into
normal brain functioning, as well as the pathophysiology and potential new treatments of
stress-related neuropsychiatric disorders.
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AMPA
receptor
NMDA
receptor
CB1
+
+
–
Second
messengers
Endocannabinoid
production
Direct genomic
effect
Glucocorticoids
Glucocorticoid
receptor
Membrane
glucocorticoid
receptor
Non-genomic
effect
Indirect genomic
effect
Glutamate
Vesicle
Presynaptic
neuron
Postsynaptic
neuron
Nucleus
Mitochondrion
Mineralocorticoid
receptor
Review will mainly address the effects of stress and
glucocorticoids on the glutamatergic neurotransmit-
ter system within the PFC (BOX1). However, it must be
acknowledged that a host of neurotransmitter and neuro-
modulatory systems in various brain regions have been
shown to be crucial in mediating the effects of stress (see
REFS10,18,19 for recent reviews), with some having very
clear effects on glutamatergic neurotransmission20.
Glutamatergic neurotransmission occurs predomi-
nantly within the confines of a tripartite synapse (FIG.1).
Several points of regulatory control within the synapse
— including basal and stimulated presynaptic glutamate
release, postsynaptic receptor trafficking and function,
and transporter-mediated uptake and recycling of glu-
tamate through the glutamate–glutamine cycle — are
sensitive to regulation by stress and glucocorticoids.
Here we review studies exploring the effects of stress
and glucocorticoids on each of these components of the
synapse, and attempt to synthesize the findings to under-
stand how stress can have beneficial effects on cognitive
function, but can also result in noxious effects that in
turn might lead to the development of neuropsychiatric
disorders.
The glutamate tripartite synapse
In addition to its role as the major excitatory neuro-
transmitter in the brain, glutamate is a key intermedi-
ary metabolite in the detoxification of ammonia and a
building block used in the synthesis of peptides and pro-
teins. Consistent with its multiple intracellular functions,
glutamate is present at extremely high concentrations
within the cells of the CNS. The high concentrations of
intracellular glutamate require that extremely tight regu-
latory processes be in place to limit extracellular levels
Box 1 | Adrenal steroids and neurotransmission
Glucocorticoids are released from the adrenal glands. Basal release
varies in a diurnal pattern, and release increases several fold after
exposure to a stressor. Glucocorticoids can bind, with different affinities,
to glucocorticoid and mineralocorticoid receptors, which are expressed
throughout the brain and seem to exist in both membrane-bound form
and nuclear form. Adrenal steroids can have both rapid and delayed
effects. The effects can result from non-genomic mechanisms (mediated
by membrane receptors, see the figure), indirect genomic mechanisms
(mediated by membrane receptors and second messengers, see the
figure) and genomic mechanisms (mediated by cytoplasmic receptors
that move to the nucleus and act as transcription factors, see the
figure)193,194, as seems now to be the case for all steroid hormones195,196.
Although mineralocorticoid and glucocorticoid receptors seem to
mediate many of these effects197,198, other membrane-associated
receptors, including G-protein-coupled receptors, may also be involved in
some of these actions49,199–201. In addition, activated glucocorticoid
receptors can translocate to mitochondria and enhance their calcium
buffering capacity202,203.Glucocorticoids rapidly induce glutamate release
in the hippocampus through a mechanism that is absent when the
mineralocorticoid receptor is deleted and that may involve a membrane-
associated form of the mineralocorticoid receptor42,204. An indirect way by
which glucocorticoids can influence neurotransmission (glutamatergic, as
well as GABAergic, cholinergic, noradrenergic and serotonergic) is
through crosstalk with the endocannabinoid system205. They rapidly
stimulate endocannabinoid production in the brain, whereupon
endocannabinoids bind to cannabinoid receptor 1 (CB1) and transient
receptor potential cation channel subfamily V member 1 (TRPV1), and
inhibit neurotransmitter release206,207 (see the figure). Although a
G-protein-coupled receptor is implicated in endocannabinoid
production208, there is also evidence for a mechanism blocked by Ru486 —
a selective antagonist of the classical cytoplasmic glucocorticoid receptor
— in the rapid actions of glucocorticoids in prefrontal cortex209.
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mGluR2
mGluR3
mGluR1
or 5
SNARE
Glutaminase
Gln
Glu
vGluT
Glucocorticoid
receptor
AMPAR
NMDAR
Ca2+
Ca2+ Na+
Glu
Glu
Glu
Gln
Gln
Glial cell
EAAT1 or 2
EAAT3
Presynaptic
neuron
Postsynaptic
neuron
Gln synthetase
Glu
Kinases and
phosphatases
SNARE complex
Soluble NSF
(N-ethylmaleimide-sensitive
factor) attachment protein
(SNAP) receptor complex.
and modulate glutamate receptor activity in order to
ensure optimal neurotransmission and prevent potential
excitotoxicity (FIG.1).
Glutamate can be synthesized denovo from glucose
in astrocytes via the Krebs cycle, followed by transami-
nation or reductive amination of α-oxoglutarate, and it
can be recycled through the glutamate–glutamine cycle21.
Exocytotic vesicular release of glutamate, which underlies
the vast majority of excitatory neurotransmission in the
brain, is a strictly regulated process in which the synaptic
vesicles that store glutamate merge and then fuse with the
presynaptic membrane in response to stimulation. In glu-
tamatergic synapses, presynaptic terminals are normally
associated with specialized postsynaptic structures (den-
dritic spines), unlike synapses at which monoaminergic
neurotransmitters (dopamine, noradrenaline, adrenaline,
serotonin and histamine) are released.
The core of the presynaptic machinery for vesicular
neurotransmitter release, including glutamate release,
is the so-called SNARE complex. The SNARE complex is
formed by the interaction of two synaptic membrane
proteins (syntaxin 1 or syntaxin 2 and SNAP25) and a
vesicular protein (synaptobrevin 1 or synaptobrevin 2),
and is thought to mediate the fusion of synaptic vesicles
with the presynaptic membrane22–24.
Glutamate regulates synaptic transmission and
plasticity by activating ionotropic glutamate receptors
(AMPA and NMDA) and metabotropic glutamate recep-
tors (mGluR1 to mGluR8). The number and stability of
these receptors at the synaptic membrane is an impor-
tant factor in determining excitatory synaptic efficacy.
Several mechanisms have been proposed to control
the surface expression of NMDARs and AMPARs,
including PDZ domain-mediated interactions between
channel subunits and synaptic scaffolding proteins25–27,
clathrin-dependent endocytosis regulated by phospho-
rylation28–30, and motor protein-based transport along
microtubule or actin cytoskeletons31–33. Members of
the RAB family of small GTPases, which function as
key regulators for all stages of membrane traffic34, are
involved in the internalization, recycling and delivery of
NMDARs and AMPARs to the spine35,36. The synthesis
and degradation of postsynaptic glutamate receptors are
dynamically regulated37,38.
Glutamate is cleared from the extracellular space by
high-affinity excitatory amino acid transporters (EAATs),
which are located on neighbouring glial cells (EAAT1 and
EAAT2) and, to some extent, on neurons (EAAT3
and EAAT4)39. In glial cells, glutamate is converted into
glutamine by glutamine synthetase. Glutamine is then
transported back into the glutamatergic neuron, where
it is hydrolysed into glutamate by glutaminase21. Owing
to the lack of degradative enzymes in the synapse, uptake
by EAATs is the primary mechanism through which the
action of extracellular glutamate is terminated. The fol-
lowing sections will discuss evidence that stress and glu-
cocorticoids can influence glutamate neurotransmission
through actions at several sites within the system, namely
at the levels of glutamate release, ionotropic glutamate
receptor activity and glutamate clearance and metabolism.
Stress effects on glutamate release
Acute stress and glucocorticoids increase extracellular
glutamate levels. Glucocorticoids secreted during the
diurnal rhythm and during stress (BOX1) affect the basal
release of glutamate in several limbic and cortical areas,
including the hippocampus, amygdala and PFC40,41.
Converging lines of evidence from animal studies sug-
gest that acute exposure to stress or administration of
glucocorticoids rapidly increases glutamate release in
these brain areas40,42–45. For example, invivo microdialysis
studies have shown that exposure of rats to tail-pinch,
forced-swim or restraint stress induces a marked, tran-
sient increase of extracellular glutamate levels in the
Figure 1 | The tripartite glutamate synapse. Neuronal glutamate (Glu) is synthesized
denovo from glucose (not shown) and from glutamine (Gln) supplied by glial cells.
Glutamate is then packaged into synaptic vesicles by vesicular glutamate transporters
(vGluTs). SNARE complex proteins mediate the interaction and fusion of vesicles with the
presynaptic membrane. After release into the extracellular space, glutamate binds to
ionotropic glutamate receptors (NMDA receptors (NMDARs) and AMPA receptors
(AMPARs)) and metabotropic glutamate receptors (mGluR1 to mGluR8) on the
membranes of both postsynaptic and presynaptic neurons and glial cells. Upon binding,
the receptors initiate various responses, including membrane depolarization, activation
of intracellular messenger cascades, modulation of local protein synthesis and,
eventually, gene expression (not shown). Surface expression and function of NMDARs
and AMPARs is dynamically regulated by protein synthesis and degradation and receptor
trafficking between the postsynaptic membrane and endosomes. The insertion and
removal of postsynaptic receptors provide a mechanism for long-term modulation of
synaptic strength. Glutamate is cleared from the synapse through excitatory amino acid
transporters (EAATs) on neighbouring glial cells (EAAT1 and EAAT2) and, to a lesser
extent, on neurons (EAAT3 and EAAT4). Within the glial cell, glutamate is converted to
glutamine by glutamine synthetase and the glutamine is subsequently released by
System N transporters and taken up by neurons through System A sodium-coupled
amino acid transporters to complete the glutamate–glutamine cycle.
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Microporous filter
0
Time of superfusion (min)
Neurotransmitter release
Collection
Stimulus (90 s)
Isolated synaptosomes
36 39 45 48
a
b
c
Superfusion medium
500 nm
PFC44,45. However, it has been suggested that a large
portion of the amino acid neurotransmitters sampled
by microdialysis is of non-neuronal origin; that is, they
may result from reverse transporter activity and/or are
derived from glial cells46,47. Nevertheless, recent evidence
from rapid microelectrode measurements suggests that
tail-pinch-stress-induced glutamate release is largely of
neuronal origin48.
In different studies using patch-clamp recordings,
application of 100 nM corticosterone (which is the
major glucocorticoid in rodents) to hippocampal slices
rapidly enhanced the frequency of miniature excitatory
postsynaptic potentials in CA1 pyramidal neurons and
reduced paired-pulse facilitation (PPF; a form of syn-
aptic facilitation that reflects presynaptic release), sug-
gesting that corticosterone increases glutamate release
probability in this area49. This rapid action of corticos-
terone was found to be non-genomic and mediated by a
mineralocorticoid receptor located in or near the plasma
membrane49,50 (BOX1).
Stress also has an effect on depolarization-evoked
release of glutamate in the PFC and frontal cortex, as
shown in studies using isolated synaptic terminals
(synaptosomes) in superfusion. This method allows
precise and selective measurement of endogenous or
labelled neurotransmitter release (BOX2). Rats subjected
Box 2 | Measuring release of endogenous neurotransmitters from purified synaptosomes
The technique for measurement of neurotransmitter release from isolated synaptic terminals (synaptosomes) in
superfusion was originally developed by Maurizio Raiteri and co-workers at the University of Genova210,211. The problem
they faced was that when neurotransmitter release is evoked from a population of synaptosomes or cells in bulk (that is, in
a test tube), any released molecule will hit receptors and transporters on the same terminal and on neighbouring terminals.
Release of a neurotransmitter (for example, glutamate) elicits a chain reaction that ultimately results in a change in the
release of that neurotransmitter (in this example, glutamate), as well as in the release of other neurotransmitters (such as
serotonin, noradrenaline, and so on). The problem was solved by applying a thin layer of semi-purified or purified
synaptosomes (see the figure, part a) on a microporous filter and applying a constant up–down superfusion to the sample
(see the figure, part b). Through this method, any released endogenous transmitters and modulators are immediately
removed by the superfusion medium before they can be taken up by transporters and activate autoreceptors or
heteroreceptors on synaptic terminals. Reuptake can therefore not occur and indirect effects are minimized or prevented.
During superfusion, all of the presynaptic targets (such as transporters, receptors, channels and enzymes) can be
considered virtually free of endogenous ligands; each of these targets can
therefore be studied separately by adding the appropriate ligand at the
desired concentration to the thin layer of synaptosomes. Any observed
effects on the release of one neurotransmitter can reasonably be attributed
to direct actions at the terminals storing that neurotransmitter. Today,
superfused synaptosomes represent the method of choice for the
functional characterization of the properties of a particular family of
nerve endings.
In a typical experiment for measuring the release of endogenous amino
acids such as glutamate or GABA, synaptosomes are layered in a
thermostated superfusion chamber and the sample is continuously
superfused for 36minutes with isotonic buffered solution to reach
stabilization of basal release. Then, the collection of samples begins, with
the first 3minutes representing basal release of neurotransmitter.
At 39minutes, a stimulus, such as depolarizing
concentrations of KCl (15–25 mM), a calcium
ionophore (ionomycin) or a receptor agonist, is
applied for 90seconds. Collection of samples
is protracted up to 48minutes, with the evoked
release-containing sample followed by one more
3-minute basal release sample (see the figure,
part c). Concentrations of released amino acids in
the perfusate samples are successively measured
by HPLC (high-performance liquid
chromatography).
Over the years, this method has been used by
many authors to distinguish exocytotic release
from release that is due to inversion of
neurotransmitter transporters, and to measure
changes in release induced by presynaptic
receptors. Recently, this method revealed that
antidepressant drugs reduce the release of
glutamate in the hippocampus (in rats kept
under basal conditions) and prevent the
increase induced by acute stress in prefrontal
and frontal cortex51,212.
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Acute stress
Basal
SNARE
proteins
Corticosterone
Glucocorticoid
receptor
Mineralocorticoid
receptor
Glutamate
??
Learned helplessness
Reduced attempts to avoid
aversive stimuli in response to
prior exposure to unavoidable
stressors. Learned helplessness
decreases after antidepressant
administration.
FM1‑43
FM1-43 is an amphiphilic
fluorescent dye that can
intercalate into the
phospholipid bilayer of
biological membranes, allowing
the staining of presynaptic
vesicles.
to acute footshock stress in a paradigm that induces
learned helplessness51 showed a marked, rapid change in
the depolarization-evoked release of glutamate52. The
increased release of glutamate in PFC and frontal cor-
tex was dependent on glucocorticoid receptor activa-
tion. The short latency of the effect suggested that the
receptor acted non-genomically, although the results of
patch-clamp recordings (see below) are also compatible
with the timing of genomic actions. Thus, both genomic
and non-genomic pathways may be involved in the effect
of stress on glutamate release. A similar rapid effect of
corticosterone, mediated by glucocorticoid receptors,
has been shown in synaptosomes isolated from rat
hippo campus53. As shown by recent findings54, recruit-
ment of endocannabinoid signalling could be involved
in the enhancement of glutamate release induced by
corticosterone.
The method of synaptosomes in superfusion involves
using synaptic terminals detached from whole tissue.
Measuring release of endogenous glutamate can also be
performed in slices of whole PFC tissue, in which the
neural circuitry is preserved. Patch-clamp recordings
from PFC slices from rats subjected to footshock stress
showed that exposure to stress increased the amplitude of
spontaneous excitatory postsynaptic potentials in pyram-
idal neurons, an effect that was abolished by pretreating
the rats with the antidepressant desipramine52. Moreover,
PPF and its calcium-dependence were decreased in PFC
slices from stressed rats. Combined, these results are con-
sistent with increased glutamate release, as well as with
increased activation of postsynaptic ionotropic glutamate
receptors, in the PFC of stressed rats.
In principle, the acute-stress-induced enhance-
ment of stimulus-evoked release of glutamate may be
achieved by increasing the number of synaptic vesicles
that are already docked to the membrane and ready for
release — the readily releasable pool (RRP) of vesicles
— or by increasing the probability of release of syn-
aptic vesicles, or both55–58. At the level of presynaptic
machinery, footshock stress induced an increase in the
number of SNARE complexes bound to the presynaptic
membrane from PFC neurons52 (FIG.2), suggesting that
at least the first mechanism is involved. Indeed, induc-
ing glutamate release with hyperosmotic sucrose from
synaptosomes in superfusion from the PFC and fron-
tal cortex of rats exposed to footshock stress revealed
that the RRP was about twofold that of control rats59.
Preliminary data obtained using total internal reflection
fluorescence microscopy to measure the recruitment
to the membrane of synaptic vesicles labelled with the
styryl dye FM1-43 also suggest a greater RRP after
invitro application of corticosterone to PFC and frontal
cortex synaptosomes59.
Interestingly, the effect of acute stress on depolar-
ization-evoked glutamate release in the PFC could
be prevented by treating the rats with various classes
of antidepressant drugs, each with different primary
mechanisms of action, for 2weeks before the stress
exposure52. The mechanism whereby antidepressant
drugs block the presynaptic effect of stress on depolari-
zation-evoked glutamate release is unknown at present.
Stress-induced serum corticosterone levels were similar
in antidepressant-treated and untreated rats, suggest-
ing that the drugs do not alter corticosterone release.
Figure 2 | Acute stress rapidly enhances glutamate release in prefrontal and frontal cortex. Acute footshock
stress enhances depolarization-evoked release of glutamate from presynaptic terminals of rat prefrontal and frontal
cortex52. The acute stress response involves a rapid increase of circulating levels of corticosterone, which binds to
membrane-located glucocorticoid receptors. This induces a rapid glucocorticoid receptor-mediated increase of
presynaptic SNARE protein complexes (which mediate fusion of synaptic vesicles) in the presynaptic membrane52.
Because the number of SNARE complexes per vesicle is reputed to be constant, this suggests that acute stress induces an
increase of the readily releasable pool of glutamate vesicles. The signalling pathways downstream of glucocorticoid
receptor activation that induce the increase of the readily releasable pool are unknown (as indicated by ‘?’).
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Instead, they might affect intracellular signalling
downstream of glucocorticoid receptor activation by
corticosterone or act directly on the glutamate release
machinery. However, the number of SNARE complexes
was increased in all stressed rats, regardless of whether
they had been previously treated with antidepressants
or not. This suggests that the antidepressant drugs acted
downstream from the assembly of SNARE complex.
For example, they could act at the level of interaction of
regulatory and fusogenic proteins with the SNARE com-
plex, modulating the function of the complex itself60–63.
It has been argued64 that the effect of antidepressants
on glutamate release in the PFC could be involved in
the long-term anxiolytic and antidepressant action of
these drugs, because they are able to dampen glutamate
release in response to acute stress52.
Chronic stress and glutamate release. As discussed
above, stress acutely enhances glutamate release in the
PFC and hippocampus. However, the effects of chronic
stress on glutamate release are still mostly unknown. It
has been shown that three repeated tail-pinch stressors
(at 2.5hour intervals) in rats produce transient gluta-
mate effluxes in the hippocampus that remain constant
in duration and magnitude, whereas in the PFC they
decrease upon subsequent applications65. These results
suggest a selective adaptation of glutamate release to
stress in the PFC. A different study tested the response
to an acute stressor in rats subjected to 21-day chronic
restraint stress. After a subsequent single stress chal-
lenge, extracellular glutamate levels (measured by
microdialysis) in CA3 remained high in chronically
stressed rats compared to naive rats that were subjected
to the same acute stressor66, suggesting an altered regula-
tion of the termination of glutamate release after chronic
exposure to stressfulstimuli.
Stress effects on ionotropic glutamate receptors
Stress and glucocorticoid effects on glutamate transmis-
sion. In addition to causing a rapid and transient increase
in presynaptic glutamate release in the PFC44,45,52, acute
stress has a delayed and sustained impact on PFC post-
synaptic glutamate receptor-mediated responses67,68.
Electrophysiological recordings have shown that both
NMDAR- and AMPAR-mediated synaptic currents are
markedly increased in PFC pyramidal neurons in various
models of acute stress67. This effect is observed >1hour
after stress, is sustained for 24hours after the cessation
of stress and can be mimicked by short-term corti-
costerone treatment invitro67–69. The acute stress- and
corticosterone-induced enhancement of basal glutamate
transmission is caused by an increased surface expres-
sion of NMDARs and AMPARs at the postsynaptic
plasma membrane67,68.
The delayed effect of acute stress or corticosterone
treatment on basal PFC glutamate transmission is
mediated by intracellular glucocorticoid receptors67,68.
This is in contrast to the rapid increase of glutamate
release in CA1 hippocampus, which is mediated by
membrane-bound mineralocorticoid receptors49,70;
the difference could be due to the low expression of
mineralocorticoid receptors in the PFC71. There are
other regional differences in the effects of stress on glu-
tamate transmission. For example, acute stress or cor-
ticosterone treatment increases AMPAR and NMDAR
responses to a similar extent in the PFC67,68, but selec-
tively enhances AMPAR-mediated currents in CA1
neurons68,72, midbrain dopamine neurons73 and nucleus
accumbens shell neurons74. Furthermore, the potenti-
ating effects of acute stress on AMPAR and NMDAR
responses in the PFC are independent of each other68,
which is different from the classic NMDAR-dependent
long-term potentiation (LTP) of AMPAR responses in
the hippocampus.
The impact of chronic stress on basal PFC glutamate
transmission is less well understood. A recent study
showed that 1week of repeated restraint or unpredict-
able stress leads to a marked reduction of AMPAR- and
NMDAR-mediated synaptic currents in PFC pyramidal
neurons from juvenile male rats, which sustains for a few
days after stress extinction75. No change in basal synaptic
currents was observed in striatal neurons, CA1 pyramidal
neurons75 or dentate gyrus neurons76. This suggests that
the PFC is more sensitive than the striatum or hippo-
campus to chronic stress, perhaps especially during the
adolescent period, when this region is still undergoing
substantial development8.
In the hippocampus9,71 and PFC, stress also affects
synaptic plasticity — that is, the ability to potentiate
(LTP) or depress (long-term depression (LTD)) the
efficacy of glutamate transmission. Acute stress inhibits
LTP in the amygdala–PFC pathway, in parallel with the
suppression of hippocampal LTP77. The acute stress-
induced impairment of LTP in the hippocampus–PFC
pathway is prevented by antidepressant treatment78 or
glucocorticoid receptor blockade79. Moreover, prior
stress exposure prevents the ability of a second epi-
sode of stress to suppress LTP in the PFC80 — a form
of emotional metaplasticity that forms the neural
basis of stress experience-dependent fear memory81.
Acute stress has divergent effects on LTD: it enhances
mGluR-dependent LTD in the hippocampus82, but pre-
vents serotonin-facilitated LTD induction in the PFC83.
Chronic stress impairs LTP in the thalamus–PFC path-
way84 and LTP in the hippo campus–PFC connection85,
and these effects are associated with the disruption of
PFC-dependent tasks, such as working memory and
behavioural flexibility85. Catecholaminergic facilitation
of LTP in the infralimbic region of the medial PFC is
also impaired by chronic stress and restored by post-
stress recovery86. These changes in synaptic plasticity
could be due to the altered structure of glutamatergic
synapses — such as atrophy, dendritic retraction or
spine loss — which have been associated with chronic
stress85,86 (BOX3). Alternatively, they could be due to
chronic-stress-induced loss of glutamate receptors
and diminished glutamate transmission in PFC neu-
rons. In line with this view, the synaptic inhibition
in the medial PFC and the fear extinction deficit that
have been observed in rats with repeated early stress
exposure are ameliorated by the NMDAR agonist
-cycloserine87.
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Prefrontal cortex
and hippocampus
Amygdala and
orbitofrontal cortex
Control
Chronic
stress
b
Synaptic
enhancement
Synaptic
suppression
Excitotoxicity
Dose or time
Receptor binding
a
Control
Chronic
stress
Stress and glucocorticoid effects on glutamate receptor
trafficking and mobility. Emerging evidence shows that
AMPARs and NMDARs undergo dynamic exocytosis–
endocytosis and lateral diffusion — processes that play
a key part in controlling excitatory synaptic efficacy88,89.
This suggests that stress and glucocorticoids may affect
glutamate transmission through altering glutamate recep-
tor trafficking and mobility. A glucocorticoid receptor-
mediated, slowly developing increase in the surface
mobility of GluR2-containing AMPARs has been found
in cultured hippocampal neurons after cortico sterone
treatment, which may underlie the facilitating effect
of glucocorticoids on the recruitment or endo cytosis of
AMPARs during bi-directional synaptic plasticity90,91.
Consistent with this possibility, mice trained in the spa-
tial water maze task under stressful conditions show
enhanced synaptic expression of AMPAR GluR2 sub-
units in the hippocampus compared to those trained
under non-stressed conditions. This enhanced expres-
sion may underlie the facilitation of spatial learning and
memory by stress in these mice92. In the rat PFC, the
surface expression of NMDAR and AMPAR subunits,
as well as the density of synaptic NMDAR and AMPAR
clusters, is substantially elevated by acute stress or a short
corticosterone treatment67,68. This suggests that the acute
stress-induced synaptic potentiation in the PFC may be
attributed to the increased delivery of glutamate recep-
tors from intracellular or extrasynaptic surface pools to
the synaptic membrane.
The impact of chronic stress on postsynaptic glu-
tamate receptors in the PFC (and other brain areas) is
less well understood (see Supplementary informationS1
(table)). A history of chronic corticosterone exposure has
been found to impair fear extinction in rats, with an asso-
ciated reduction of NR2B (also known as NMDAR2B or
GRIN2B) and GluR2 and/or GluR3 subunit expression
selectively in the ventromedial PFC93. Recently, it was
shown that repeated restraint or unpredictable stress in
rats causes a loss of surface AMPAR and NMDAR sub-
units in PFC neurons75, which contrasts with the facili-
tating effect of acute stress on glutamate receptor surface
expression67,68. The level of total GluR1 and NR1 (also
known as NMDAR1 or GRIN1) subunits in the PFC is
also markedly reduced by exposure to repeated stress75.
Thus, disrupted membrane trafficking and/or altered
degradation or synthesis of glutamate receptors may
contribute to the loss of PFC glutamate transmission in
chronically stressedanimals.
Intracellular signalling underlying stress and gluco-
corticoid effects on glutamate receptors. The classical
glucocorticoid receptor is a ligand-inducible nuclear
transcription factor94. The delayed potentiating effect
of short-term corticosterone treatment on excitatory
postsynaptic responses in the PFC is abolished by gluco-
corticoid receptor antagonists and inhibitors of gene
transcription or protein translation68, suggesting that it
is a glucocorticoid receptor-mediated genomic effect.
Serum- and glucocorticoid-inducible kinases (SGKs), a
family of immediate early genes activated by glucocorti-
coid receptors, have been found to control the enhancing
Box 3 | Structural changes induced by stress
Until recently, much of our information on stress, excitatory amino acids (EAAs) and
synaptic function has come from studies on the hippocampus, which expresses both
mineralocorticoid and glucocorticoid receptors. In the hippocampus, EAAs and
glucocorticoids mediate biphasic effects on structure and function (see the figure, part a).
Acutely (that is, over hours), low to moderate physiological levels of adrenal steroids and
EAAs enhance synaptic function and certain types of memory, whereas higher levels of
both mediators have the opposite effect213. More chronically (that is, over days to weeks),
adrenal steroids and EAAs mediate adaptive plasticity involving spine synapse turnover,
dendritic shrinkage and suppression of adult neurogenesis in the dentate gyrus7. However,
when there is a sudden insult, such as a seizure, stroke or other head trauma, EAAs and
glucocorticoids induce permanent, irreversible hippocampal damage214.
Acute and chronic stress also induce structural changes in other brain areas. Chronic
stress causes shrinkage of neurons in the medial prefrontal cortex (PFC), simplification of
dendrites and reduction of spine density, whereas the same stress regimen causes the
growth of neurons in the basolateral amygdala and orbitofrontal cortex (see the figure,
part b)5,6. With the cessation of stress, these alterations are reversible215,216, except
possibly in the basolateral amygdala, where changes persisted for at least 30days after
chronic stress217. Moreover, age is a factor in recovery, as the ageing medial PFC fails to
show recovery in the same timeframe as occurs in younger animals218.
Structural plasticity can also occur after acute stress. A single traumatic stressor causes
basolateral amygdala neurons to grow new spines over the next 10days, but there is no
growth of dendrites219. Furthermore, a single, high dose of injected corticosterone causes
delayed dendritic growth over the next 10days220, mimicking the effects of chronic
stress, although we do not know what happens to spines on those dendrites.
As to the mechanism underlying these effects, we know most about the hippocampus.
Here, EAAs and glucocorticoids synergize to produce the effects summarized in part a of
the figure221. EAA transporters in astrocytes and neurons play an important part in
this160,222. In addition, in the CA3 region of the hippocampus, the effects of chronic stress
on the shrinkage of dendrites are mediated in part by brain-derived neurotrophic factor
(BDNF)223, whereas in the CA1 region of the hippocampus, the effects of chronic stress on
the loss of spines are mediated in part by tissue plasminogen activator secretion by
EAA-releasing neurons224 and by BDNF223. Effects of chronic stress on dendrite shrinkage
in CA3 are blocked by NMDA receptor blockers221, and NMDA receptor blockade also
prevents chronic-stress-induced shrinkage of medial PFC neurons225.
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Corticosterone
Early endosome
RAB4
SGK
GDI
GDI
P
AMPAR
Glucocorticoid
receptor
Nucleus
GRE
Nature Reviews | Neuroscience
NMDAR
effect of acute stress on glutamate receptor trafficking
and function in the PFC68 (FIG.3). The transcription, sub-
cellular localization and enzymatic activity of SGKs are
under the stringent regulation of various stimuli, such
as oxidative stress or hormones95. SGKs participate in a
wide variety of physiological functions, including activa-
tion of ion channels and carriers, regulation of transport,
gene transcription, neuroexcitability, cell proliferation
and apoptosis96. Interestingly, during the water maze
learning task, SGK1 expression levels are four times
higher in the hippocampus of fast-learning rats than in
the hippocampus of slow-learning rats, and enhanced
SGK expression in CA1 facilitates memory consolida-
tion of spatial learning in rats97. Thus, SGKs potentially
have a crucial role in glucocorticoid-induced memory
facilitation by increasing the abundance of glutamate
receptors in the synaptic membrane of neurons in limbic
regions controlling cognition67,68,92.
The key molecule linking glucocorticoid receptors
and SGK activation to the increased surface expres-
sion of NMDARs and AMPARs following acute stress
is RAB4 (REFS68,69), a member of the RAB family that
mediates receptor recycling between early endosomes
and the plasma membrane98. RAB proteins coordinate
all of the intracellular transport steps in the exocytic
and endocytic pathways99. Many RAB proteins are regu-
lated by the GDP dissociation inhibitor (GDI)100, which
functions as a cytosolic chaperone of RAB101. SGK phos-
phorylates GDI and thereby promotes the formation
of the GDI–RAB4 complex, thus facilitating the func-
tional cycle of RAB4 and RAB4-mediated recycling of
AMPARs to the synaptic membrane69 (FIG.3).
Whether other signalling pathways are also involved
in effects of stress and glucocorticoids on glutamate
receptors awaits investigation. In the hippocampus, a
single corticosterone injection fails to upregulate Sgk1
mRNA102. However, acute stress has been found to trig-
ger activation of the mitogen-activated protein kinase
(MAPK)–early growth response protein 1 (EGR1) path-
way through a glucocorticoid receptor-mediated genomic
mechanism103, and inhibition of the hippocampal MAPK
pathway abolishes the glucocorticoid-induced increase
in contextual fear conditioning103. Moreover, in the PFC
— but not the hippocampus — of mice, acute restraint
stress causes an increase in the expression of Arc (activity-
regulated cytoskeletal-associated protein)104, an immedi-
ate early gene that has a key role in activity-dependent
synaptic modification105,106. In addition, changes in adhe-
sion molecules could potentially be involved in the effect
of short-term glucocorticoids on excitatory synapses92.
The intracellular signalling pathway that mediates the
effect of chronic stress on glutamate receptors remains
largely unknown. One key mechanism for remodelling
synaptic networks and altering synaptic transmission is
post-translational modification of glutamate receptors
and their interacting proteins through the ubiquitin
pathway at the postsynaptic membrane107. Recently it
was found that the loss of glutamate receptors in rat PFC
neurons after repeated stress is attributable to increased
ubiquitin–proteasome-dependent degradation of GluR1
and NR1 subunits75.
Implications for cognitive function. Given the role of
glutamate receptor trafficking in learning, memory and
other behaviours108,109, it is plausible that glucocorticoids
regulate PFC-mediated cognitive processes by influenc-
ing postsynaptic glutamate receptor channels. Indeed,
the glucocorticoid receptor–SGK-induced enhance-
ment of PFC glutamate transmission may underlie
the facilitated working memory induced by acute stress:
exposing rodents to an acute stressor improves their per-
formance in a working memory task, and this effect is
abolished by blocking glucocorticoid receptor or SGK
function in the PFC67,68. This finding fits well with acute
stress- or glucocorticoid-induced facilitation of work-
ing memory (which involves the PFC) and declarative
memory (which involves the hippocampus) observed
in humans110–112. By contrast, chronic stress or gluco-
corticoid treatment impairs PFC-dependent cognitive
functions in rats5,113 and humans114,115, and likewise
causes deficits in hippocampus-dependent cognitive
processes116. It awaits investigation whether the suppres-
sion of PFC glutamate transmission by repeated stress
Figure 3 | Stress induces changes in glutamate
receptor trafficking and function in the prefrontal
cortex. In response to acute stress, activation of
glucocorticoid receptors triggers the upregulation of
transcription of the genes encoding serum- and
glucocorticoid-inducible kinase 1 (SGK1) and SGK3
(REF.68). SGK1 and SGK3 phosphorylate GDP dissociation
inhibitor (GDI) and thereby increase the formation of GDI–
RAB4 complexes69. Consequently, RAB4-mediated
recycling of NMDA receptors (NMDARs) and AMPA
receptors (AMPARs) from early endosomes to the plasma
membrane is enhanced, and this results in increased
glutamate receptor expression at the synaptic membrane
and potentiated glutamate transmission67,68. GRE,
glucocorticoid response element.
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underlies the working memory impairment and other
cognitive symptoms that are often observed in stress-
related mental disorders.
Stress effects on clearance and metabolism
Most studies examining the effects of stress on brain
structure and physiology focus on neurons. However,
emerging data suggest that stress may also affect glial cell
function, including glutamate clearance and metabolism
in these cells. These data are discussedbelow.
Glutamate transporters on glial and, to a lesser extent,
neuronal membranes rapidly bind synaptic glutamate,
thereby influencing synaptic transmission and plasticity117.
The locations of the transporters within the tripartite
synapse are optimized for preventing glutamate spill-
over and activation of extrasynaptic glutamate recep-
tors. Consistent with this function, in the hippocampus,
glial glutamate transporter activity influences the level
of stimulation of peri- and extrasynaptic NMDARs and
mGluRs, but has little direct effect on synaptic AMPA-
mediated excitatory postsynaptic potentials118. The effects
of astrocytic remodelling on glutamatergic neurotrans-
mission in the hypothalamus of lactating rats provides
a clear example of how reduced astrocytic coverage of
synapses can have dramatic effects on extrasynaptic
glutamatergic neurotransmission119. Modulation of the
expression and function of EAAT2 (the major glutamate
transporter, expressed predominantly in glia) can affect
neuronal vulnerability to excitotoxic events39, which is
thought to be mediated by the relative activation of extra-
synaptic to synaptic NMDARs120–125. Moreover, modula-
tion of EAAT2 expression affects hippocampal LTD126. As
the transporters are generally highly efficient in clearing
glutamate from the extracellular space39,127, any effects of
altered EAAT function are likely to be most pronounced
under conditions of elevated glutamate release, such as
under stress. Considering that individual astrocytes serve
large numbers of synapses, with minimal overlap in the
synapses served by neighbouring astrocytes128,129, the fail-
ure of a single astrocyte could impair glutamate removal
at thousands of synapses118.
Effects of stress and glucocorticoids on glial cell number.
Studies published over a decade ago revealed the poten-
tial contributions of glial cell pathology to stress-related
psychiatric disorders such as major depressive disor-
der and bipolar disorder. For example, PFC regions of
post-mortem brain samples from individuals suffering
from mood disorders showed markedly reduced glial
cell numbers and density130–132. Depressed subjects also
show reduced immuno-staining of glial fibrillary acidic
protein (GFAP) — the main intermediate filament pro-
tein in mature astrocyte — in the PFC and other brain
regions, including the amygdala and cerebellum133–137.
Classically, GFAP has been used as a marker for mature
astrocytes, but more recent studies that highlight the
complex relationship between GFAP expression and
various astrocytic functions suggest that the expression
may be heavily physiologically regulated138. It is there-
fore unclear whether the findings in post-mortem brain
tissue from patients reflect a loss of GFAP-expressing
cells or a reduction in the amount of GFAP expressed by
the cells. As astrocytes have a central role in amino acid
neuro transmitter metabolism, these findings — which
are suggestive of glial cell pathology — were rapidly
associated with emerging reports of abnormal GABA
and glutamate content in the brains of patients with
mood disorders139,140.
Rodent models assessing the impact of stress on
glial cells have largely focused on the effects of chronic
stress. Chronic unpredictable stress was associated
with reduced proliferation of glial progenitor cells141,
decreased numbers of GFAP-positive cells and reduced
expression of GFAP in the prelimbic cortex141,142 (FIG.4).
Rats exposed to early life stress had a reduced density of
GFAP-immunoreactive astrocytes in the frontal cortex
in adulthood, demonstrating the potential long-term
effects of stress on glial cells143. Chronic stress-induced
reductions in GFAP-immunoreactive astrocyte levels
were also found in the hippocampus in rats and tree
shrews144,145. Another recent study that used a shorter-
term repeated stress exposure accompanied by a blast-
induced traumatic brain injury found inflammation
and increased GFAP immunoreactivity in the PFC and
hippocampus in animals that had experienced both the
chronic stress and the trauma but not in animals that
had been exposed to the stress alone146. This finding sug-
gests that physical injury or inflammation may stimulate
a region of reactive gliosis that can be associated with
an increased GFAP expression138. This reactive gliosis-
associated increase in GFAP expression could provide an
explanation for the increased GFAP expression observed
under certain stress conditions, such as those involving
repeated restraint stress147.
Glucocorticoids can alter the level and expression
of GFAP in the PFC and other regions in rat brain,
with both short- and long-term corticosterone treat-
ments resulting in >20% reduction in GFAP levels148,149.
These changes were paralleled by changes in GFAP
mRNA expression, indicating a genomic effect. This
effect of glucocorticoids was not generalized to other
astrocytic proteins or major structural neuronal pro-
teins148. However, later studies that reported increased
levels of GFAP expression in the hippocampus after
chronic glucocorticoid treatment150,151 suggest that the
effects are diverse and complex, with glucocorticoids
potentially having regional and dose-related effects on
GFAP expression.
Effects of stress and glucocorticoids on glial cell gluta-
mate uptake. Changes in GFAP expression in the brains
of stressed animals do not provide direct evidence of
altered glutamate clearance (and, by extension, gluta-
mate neurotransmission). However, there is evidence to
suggest that GFAP can modulate glutamate uptake activ-
ity through effects on transporter trafficking and surface
expression152. A few studies have provided more direct
measures of the effect of stress on glutamate uptake.
An early study that used synaptosomal preparations
from acutely restrained rats suggested that acute stress
increases glutamate uptake in the frontal cortex and
hippo campus153. Later studies have yielded mixed results
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Nature Reviews | Neuroscience
SNARE
Glutaminase
Gln
Glu
vGluT
AMPAR
NMDAR
Ca2+
Ca2+ Na+
Glu
Glu
Glu
Gln
Gln
Glial cell
EAAT2
EAAT3
Presynaptic
neuron
Postsynaptic
neuron
Spillover
Excitotoxicity
Reduced Glu
clearance
↓GFAP expression
↓GFAP+ glial cells
GFAP
Reduced flux
Gln synthase
Glu
mGluR1
or 5
EAAT1
in the hippocampus following acute stress exposure,
showing either a glucocorticoid-mediated suppression
of glutamate uptake154 or no effect on uptake155.
In relation to chronic stress, one study showed a
decrease in cortical glutamate uptake following 21days
of restraint-stress exposure156. A recent study also found
a reduction in hippocampal glutamate clearance in hip-
pocampal slice preparations from chronically stressed
rats as well as evidence of increased glutamate release
from hippocampal synaptosomes157. Another recent
study using slice preparations from hippocampal, stri-
atal and PFC regions reported no change in glutamate
clearance immediately or 24hours after various types of
footshock exposure. However, in this study, glutamate
uptake was increased in hippocampal slices taken from
helpless animals immediately after footshock exposure,
whereas reduced rates of glutamate uptake in all three
brain regions was reported in helpless animals 21days
after exposure158. This suggests a potential biphasic time
course of the regulation of glutamate uptake following
stress exposure. Yet another study, which demonstrated
a negative correlation between EAAT2 expression levels
in the hippocampus, occipital and retrosplenial granu-
lar cortex of rats and the level of helplessness 5weeks
after exposure to footshock stress159, provides evidence
that the stress-related effects on EAAT2 function are
long-lasting and associated with behavioural changes.
Together with the findings discussed above, these data
suggest that chronic stress impairs both the mechanisms
that regulate glutamate release and the mechanisms that
regulate glutamate clearance. These longer-term effects
on the balance of glutamate release and uptake follow-
ing chronic stress could contribute to the finding of
sustained elevations of extracellular glutamate concen-
trations in the hippocampus of rats subjected to chronic
stress, as discussedabove66.
Emerging evidence suggests that glucocorticoids may
have a role in mediating the effects of stress on EAAT2
regulation. Rats chronically exposed to high levels of
glucocorticoids exhibited increases in the expression
of GLT1b (an isoform of EAAT2 (which is also known
as GLT1)) in the hippocampus160. In addition, activation
of glucocorticoid receptors increased EAAT2 expression
and enhanced glutamate uptake in primary astrocytes
derived from cortical tissue161. However, the complex
and seemingly biphasic regulation of EAAT2 by gluco-
corticoids is highlighted by the fact that EAAT2 mRNA
expression was increased by adrenalectomy and
Figure 4 | Chronic stress affects glial cells and glutamate metabolism. Accumulating evidence suggests that chronic
stress has significant effects on glial cell function. Several studies have demonstrated decreases in the expression of glial
fibrillary acid protein (GFAP) and in the number of GFAP-expressing glial cells in the hippocampus and prefrontal cortex
following exposure to chronic stress142. Chronic stress may also impair the ability to effectively clear synaptic glutamate (Glu)
through glial excitatory amino acid transporters (EAATs). This may lead to glutamate spillover and, ultimately, increased
activation of extrasynaptic glutamate receptors, resulting in excitotoxicity, a process that has been proposed to occur in
several neurodegenerative disorders127,226 and possibly after exposure to chronic stress171. Finally, chronic stress may decrease
the rates of flux through the glutamate–glutamine (Gln) cycle, resulting in reduced glutamate metabolism171. AMPAR, AMPA
receptor; mGluR, metabotropic glutamate receptor; NMDAR, NMDA receptor; vGluT, vesicular glutamate transporter.
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inhibited by subsequent glucocorticoid replacement,
whereas exposure to chronically elevated levels of gluco-
corticoids increased EAAT2 protein expression through-
out the hippocampus160.
Other processes could also mediate the stress-
induced effects on glutamate uptake. Highly conserved
promoter sequences, including those for epithelial
growth factor (EGF), transforming growth factor-α
(TGFα) and tumour necrosis factor-α (TNFα), have
been identified in the regulatory region of EAAT2
in rodents and humans162. Circulating TNFα levels in
particular increase with chronic stress163 and have been
shown to downregulate astrocyte-mediated glutamate
transport through the direct downregulation of EAAT2
(REFS164,165). Invitro studies also show that neuronal
activity is linked to genomic and non-genomic regula-
tion of astrocyte-specific synaptic functions, such as
trafficking and membrane stabilization or clustering of
EAAT2 protein166,167. Thus, extracellular levels of gluta-
mate can act to rapidly increase the function of glutamate
transporters to limit excitotoxicity due to excessive gluta-
mate release. Interestingly, post-mortem studies showed
lower mRNA expression levels of SCL1A2 and SCL1A3
(the genes encoding the glial glutamate transporters) in
the PFC168 and locus coeruleus169 of patients with major
depressive disorder, as well as lower EAAT2 immuno-
reactivity in the orbitofrontal cortex of depressed
individuals compared with controls136.
Effects of stress on glutamate metabolism. Post-mortem
studies of the PFC of depressed individuals have shown
reduced levels of glial expression of glutamate-ammonia
ligase (GLUL) — the gene that encodes glutamine syn-
thetase (which converts glutamate into glutamine)168,170
— and a trend for reduced glutamine synthetase immu-
noreactivity in the orbitofrontal cortex of patients with
major depressive disorder compared to controls136.
However, few studies have examined the effects of stress
on glutamine synthetase regulation. Rats exposed to
chronic unpredictable stress showed reductions in glu-
tamate–glutamine cycling in the PFC171. However, there
was no evidence of reduced glutamine synthetase expres-
sion, suggesting that other, non-transcriptional regula-
tory factors may mediate the stress-induced changes. It is
also possible that other steps in the metabolic cycle, such
as the decreased uptake of glutamate into the glial cell, as
discussed above, may contribute to the stress effect on
glutamate metabolism.
In summary, the evidence suggests that acute stress
and acute glucocorticoid treatments induce adaptive
changes that lead to increased glutamate clearance,
thereby preventing spillover of the excessive release
of presynaptic glutamate into the extrasynaptic space.
However, chronic stress, and possibly chronic glucocor-
ticoid treatment, seem to result in sustained glial cell
alterations and reduced rates of amino acid neurotrans-
mitter cycling in the PFC, suggesting that chronic stress
causes a reduced glutamate clearance capacity relative
to the levels of glutamate release. Increased levels of
extrasynaptic glutamate could lead to cellular damage
through activation of extrasynaptic glutamate receptors,
resulting in disruption of cellular functions and neuro-
degeneration120. This process could be involved in the
cellular changes130,131,133,134,136,172,173 and volume reductions
that are commonly observed in the PFC and hippo-
campus of patients with stress-related disorders, such
as mood and anxiety disorders174,175. In a preliminary
report, extracellular hippocampal glutamate content, as
measured by invivo microdialysis, was correlated with
reduced hippocampal volume in individuals with seizure
disorders176, lending support to the hypothesis outlined
above, although it does not prove that the relationship
between extracellular glutamate levels and hippocampal
volumes iscausal.
Conclusions and future directions
Stress has been shown to induce complex structural
changes in various brain regions (BOX3). With regard
to the glutamatergic synapse, stress can have either
plasticity-enhancing effects that are associated with
improved cognition and function or noxious effects
that are associated with impaired function, depending
on the type, intensity and duration of the event, and this
may contribute to the pathophysiology of psychiatric
disorders (see Supplementary informationS1 (table)).
Recent studies are beginning to elucidate how stress-
induced changes in various aspects of glutamate neuro-
transmission are causally linked to each other and to the
glucocorticoid responses tostress.
Acute stress seems to have the general effect of
increasing glutamatergic neurotransmission in the PFC
and other regions associated with memory, learning
and affect by inducing both genomic and non-genomic
changes at various sites within the tripartite synapse. The
presynaptic release of glutamate is rapidly increased by
mineralocorticoid or glucocorticoid receptor-mediated
effects on the machinery that regulates glutamate release.
At the postsynaptic site, acute stress seems to increase
the surface expression and density of ionotropic glu-
tamate receptors, resulting in synaptic potentiation,
with the mechanism and timing of these effects vary-
ing between brain regions. Although few studies have
adequately examined the effects of acute stress on glu-
tamate clearance and metabolism, there seems to be
an increased expression of EAAT2 and possibly other
glutamate transporters, matching the increased synap-
tic release of glutamate following acute stress exposure.
Together, these changes could contribute to the adap-
tive stress response on cognitive functions, as demon-
strated by findings that moderate acute stress facilitates
classical conditioning177, associative learning92,178 and
working memory67,68.
Emerging studies now suggest that chronic stress
exposure has different effects on the glutamate synapse.
Data from early studies suggest that chronic stress causes
prolonged periods of stimulated glutamate release follow-
ing acute stress exposure, at least in the hippocampus.
Possibly as a compensatory response to elevated synap-
tic glutamate activity, there are changes in the surface
expression of AMPAR and NMDAR subunits that seem
to be associated with a decreased transmission efficiency
and potentially impaired synaptic plasticity. Initial rodent
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mGluR2
mGluR3
mGluR1
or 5
SNARE
Glutaminase
Gln
Glu
vGluT
AMPAR
NMDAR
Ca2+
Ca2+ Na+
Glu
Glu
Glu
Glu
Gln
Gln
Glial cell
EAAT1
or 2
Presynaptic
neuron
Postsynaptic
neuron
d
c
e
b
af
g
hCB1
Gln
synthetase
Kinases and
phosphatases
Glucocorticoid
receptor
IEGs
f
Corticosterone
GRE
studies suggest that the PFC may be specifically sensi-
tive to the stress-induced effects on postsynaptic recep-
tor function. Last, there is growing evidence from animal
studies that chronic stress has effects on glial cell mor-
phology, metabolism and function in the PFC and pos-
sibly also the hippocampus. These long-lasting chronic
stress-induced changes in glutamate transmission may
be linked to the impairments in spatial and contextual
memory performance and attentional control5,7 and the
reduced synaptic plasticity in the hippocampus–PFC
connection that have been observed in rats after chronic
stress85. The decreased ability to clear extracellular gluta-
mate as a result of impaired glial cell uptake and metabo-
lism, combined with stress-induced changes in glutamate
release and glutamate receptor function, could provide a
pathophysiological mechanism leading to many of the
structural changes (BOX3) observed in brain regions of
individuals with stress-associated psychiatric disorders,
such as mood and anxiety disorders.
These findings suggest a new line of drug develop-
ment that should be aimed at minimizing the effects
of chronic stress exposure on the function of the gluta-
matergic neurotransmitter system64,179 (FIG.5). The
hypothesis that pharmacological modulation of pre-
synaptic release of glutamate may provide a means of
preventing the effects of stress is supported by findings
from animal studies that chronic administration of clas-
sical antidepressant drugs, such as selective serotonin
re-uptake inhibitors, serotonin–noradrenaline reuptake
inhibitors, tricyclics and atypical antidepressants, reduces
the stress-induced upregulation of glutamate release in
superfused synaptosomes from the PFC and frontal cor-
tex52. Other studies have shown that drugs such as rilu-
zole180–182 and ceftriaxone183, which increase glutamate
clearance, can prevent or reverse the effects of chronic
stress and chronic glucocorticoid exposure on amino acid
neurotransmitter cycling, on glial expression within the
PFC, and on despair and anhedonia in animal models
Figure 5 | Pharmacological targets. Observations of
stress-induced effects on the glutamate (Glu) synapse
have suggested several unique forms of pharmacological
interventions for stress-related disorders such as mood
and anxiety disorders179. Drugs that modify glutamate
release (a), such as lamotrigine and riluzole, have been
shown to have antidepressant-like actions in rodent
models and in clinical trials171,227,228. In addition,
antagonists and negative allosteric modulators of the
group II metabotropic receptors (mGluR2 and mGluR3)
(b), such as MGS0039 and LY341495, have been shown to
exert antidepressant-like effects in rodents, suggesting
that a dampening of the group II mGluR-mediated
inhibition of presynaptic glutamate release could provide
a mechanism of antidepressant drug action186,190. Positive
and negative allosteric modulators of mGluR5 (c) have
been shown to possess antidepressant and anxiolytic
properties in preclinical studies186. Drugs targeting
NMDA receptors (NMDARs) (d), especially NMDA
antagonists (ketamine, RO 25-6981 and CP101606), have
demonstrated rapid and robust antidepressant-like
effects in both rodent models and clinical trials187,188.
Drugs targeting AMPA receptors (AMPARs) (e), especially
agents that potentiate the activation of AMPARs, have
both nootropic (cognition-enhancing) properties and
antidepressant-like effects in rodent models192.
Various agents that regulate glucocorticoid signalling (f)
have effects on memory and possess mood- and
anxiety-modifying properties229. Drugs such as riluzole
and ceftriaxone that indirectly facilitate glutamate
transport into glia (g), possess both neuroprotective and
antidepressant-like effects171,184,185. Considering that
endocannabinoids are reduced in the prefrontal cortex
and hippocampus in animal models of depression, and
that cannabinoid 1 receptor (CB1) stimulation in the
prefrontal cortex and hippocampus has anxiolytic and
antidepressant effects, targeted pharmacological
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Gln, glutamine; GRE, glucocorticoid response element;
IEGs, immediate early genes; vGluT, vesicular
glutamate transporter.
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Acknowledgements
M.P. is supported by the Italian Ministry of University and
Research (MIUR‑PRIN), the National Alliance for Research on
Schizophrenia and Depression (NARSAD) and the European
Union (FP6 — GENDEP Project). Z.Y. is supported by grants
MH85774 and MH84233 from the US National Institute of
Mental Health (NIMH). B.S.M. is supported by grant
MH41256 from the NIMH, Conte Center grant 5 P50
MH58911 to J.Ledoux (principal investigator at New York
University), and the MacArthur Foundation Research
Network on Socioeconomic Status and Health. G.S. is sup‑
ported by grants R01 MH081211 and 5 R01 MH071676‑05
from the NIMH, the NARSAD, the National Center for
Posttraumatic Stress Disorder of the US Department of
Veterans Affairs, and the Clinical Neuroscience Division (West
Haven, Connecticut) of the Department of Mental Health and
Addiction Services for the State of Connecticut.
Competing interests statement
M.P. and G.S. declare competing financial interests; see Web
version fordetails.
FURTHER INFORMATION
Maurizio Popoli’s homepage 1: http://users.unimi.it/DPS
Maurizio Popoli’s homepage 2: http://gendep.iop.kcl.ac.uk
Zhen Yan’s homepage: http://www.buffalo.edu/~zhenyan
Bruce McEwen’s homepage: http://www.rockefeller.edu/
research/faculty/labheads/BruceMcEwen
Gerard Sanacora’s homepage: http://psychiatry.yale.edu/
research/programs/clinical_people/trials/sanacora1.aspx
SUPPLEMENTARY INFORMATION
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