-
se hypothesis
kal1,3, Mark D. Kvarta1,3,4,and Xiang Cai1,5
edicine, 655 West Baltimore Street, Baltimore, MD 21201,
USAedicine, 655 West Baltimore Street, Baltimore, MD 21201, USA
of Maryland School of Medicine, 655 West Baltimore Street,
hool of Medicine, 655 West Baltimore Street, Baltimore, MD
21201,
ndale, IL 62901, USA
in the brain driving the range of behavioral symptoms
thatcharacterize depression is essential for developing
moreeffective treatments for this disorder and preventing
suicide.
In the search for ways to prevent, treat, and cure diseases,a
strong hypothesis can prove invaluable if it accounts forknown
etiologies, is consistent with existing human andpreclinical data
gathered across a range of modalities,makes clearly testable
predictions, explains the effective-ness of existing therapies
mechanistically, and offers guid-ance for the development of novel
prophylactic and
Feature Reviewlifetime prevalence of 712% in men and 2025% in
wom-en, and a multibillion-dollar annual economic burden inthe USA
[1,2].
The most tragic consequence of untreated depression issuicide,
attempted by as many as 8% of severely depressedpatients. According
to the Centers for Disease Control andPrevention, nearly half a
million patients receive emergencycare for suicide attempts each
year in the USA and over38 000 individuals die by intentional
self-inflicted injuries,twice as many lives as are lost to
homicide. Shockingly,23% of suicide victims were being treated with
antidepres-sants at the time [3]. In fact, only half of patients
with majordepression respond to standard-of-care
antidepressants(ADs), such as selective serotonin reuptake
inhibitors(SSRIs) [4], with 70% failing to achieve full
remission[5]. A better understanding of the nature of the
changes
mild stressors twice per day for 3 weeks.
Forced swim test: animals are placed in a tank of water until
they cease
struggling. Nave, unstressed animals have longer latencies to
cease struggling
compared with stressed animals.
Learned helplessness: animals receive a single session with
repeated
unpredictable and uncontrollable stressors (foot shocks).
Learned helplessness test: animals are placed in a chamber where
they
previously received inescapable foot shocks paired with a
conditioned
stimulus. Latency to escape from the same chamber is later
measured in
response to the conditioned stimulus.
Novelty suppressed feeding test: animals are food deprived then
placed in a
brightly lit arena with food in the center. The latency until
they venture into the
center and eat is measured. Nave, unstressed animals display a
shorter
latency compared with stressed animals. This test may reveal
more about
anxiety than about hedonic state.
Social interaction test: animals are placed in an arena with a
novel juvenile
animal held in a small cage. Time spent in the vicinity of the
cage is compared
in the presence and absence of the juvenile. Nave, unstressed
animals spend
more time in the vicinity of the cage when the juvenile is
present, whereas
chronically stressed animals do not, presumably because the
social interaction
is no longer rewarding.
Sucrose preference test: a two-bottle choice between plain water
and dilute
(1%) sucrose solution. Nave, unstressed animals drink
approximately 8090%
of their liquid from the sucrose solution, whereas chronically
stressed animals
drink nearly equally from both bottles, presumably because the
sucrose
solution is no longer rewarding.
Tail suspension test: mice are dangled by their tails until they
cease to
struggle. Nave, unstressed animals have longer latencies to
immobility
compared with stressed animals.
0166-2236/
2015 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tins.2015.03.003
Corresponding author: Thompson, S.M.
([email protected]).Keywords: glutamate; stress; ketamine;
reward; hippocampus; nucleus accumbens.An excitatory synapof
depressionScott M. Thompson1,2,3, Angy J. KallaracAdam M. Van
Dyke1,3, Tara A. LeGates1, 1Department of Physiology, University of
Maryland School of M2Department of Psychiatry, University of
Maryland School of M3Programs in Neuroscience and Membrane Biology,
UniversityBaltimore, MD 21201, USA4Medical Scientist Training
Program, University of Maryland ScUSA5Department of Physiology,
Southern Illinois University, Carbo
Depression is a common cause of mortality and morbid-ity, but
the biological bases of the deficits in emotionaland cognitive
processing remain incompletely under-stood. Current antidepressant
therapies are effectivein only some patients and act slowly. Here,
we proposean excitatory synapse hypothesis of depression in
whichchronic stress and genetic susceptibility cause changesin the
strength of subsets of glutamatergic synapses atmultiple locations,
including the prefrontal cortex (PFC),hippocampus, and nucleus
accumbens (NAc), leading toa dysfunction of corticomesolimbic
reward circuitry thatunderlies many of the symptoms of depression.
Thishypothesis accounts for current depression treatmentsand
suggests an updated framework for the develop-ment of better
therapeutic compounds.
Major depressive disorder: from a symptom-baseddescription to
biological phenotypesMajor depressive disorder (MDD) is one of the
most com-mon and costly of neuropsychiatric syndromes, with
aGlossary
Allostatic load/overload: allostasis is the concept that
homeostatic set-points
can be differentially regulated to meet different demands in the
internal and
external environment (e.g., physical or psychological stress).
Repeated
allostatic adaptation exacts a cost on the brain.
Chronic restraint stress: animals are placed in restraint tubes
for several hours
daily, repeated over several days (e.g., 4 hours/day for 1014
days).
Chronic social defeat: animals are typically placed in the home
cage of a novel
aggressor for 30 min, once daily for 3 weeks.
Chronic unpredictable stress: animals experience two bouts of
one of manyTrends in Neurosciences, May 2015, Vol. 38, No. 5
279
-
therapeutic approaches. The serotonin hypothesis of depres-sion,
formulated during the early 1960s, provides an excel-lent example,
driving the field of biological psychiatryforward and leading to
the development of SSRIs (Box 1).More recently, considerable
evidence of the involvement ofneurotrophins in depression and
antidepressant action hasaccumulated, leading to a neurotrophin
hypothesis of de-pression (Box 2). Nevertheless, these hypotheses
leavemany questions about both the causes and treatment
ofdepression.
In this review, we highlight emerging evidence of dys-functions
of excitatory synaptic transmission [6], and sug-gest how this
defect correlates with the genesis of depressionand the evidence
that serotonin and neurotrophins have arole in depression. We are
now moving beyond a symptom-based description of depression as a
single disease entityand beginning to identify biological
phenotypes that can becompared across species and across
classically definedlabels, as encouraged by the Research Domain
Criteria ofthe National Institute of Mental Health (NIMH). Thus,
asignificant goal of basic research is to identify the
neurobio-logical consequences of disease-promoting conditions at
the
involves a combination of genetic and epigenetic suscepti-bility
together with environmental risk factors, such asstress, emotional
trauma, or traumatic head injury [7], withheritable factors
contributing slightly less than half of therisk. Many SNPs and
epigenetic differences are linked toincreased risk for depression,
but no single gene candidateproduces a strong enough effect to
provide convincing mech-anistic hypotheses [8]. This reinforces the
fact that MDD is acomplex and heterogeneous collection of symptoms
causedby variations in multiple genes, each responsible for a
smalleffect on risk, that ultimately converge onto common
circuit,cellular, and molecular pathways.
Stress and depressionStressful life events are a key
environmental risk factor fordepressive disorders in genetically
susceptible individuals[9] and are suspected to be causal in many
patients.Patients who are depressed report more stressful
lifeevents and have fewer social resources compared
withnondepressed subjects [10]. Personality traits, in particu-lar
neuroticism and lack of a confidence, have also beenlinked to the
etiology of depression and may increase risk
Feature Review Trends in Neurosciences May 2015, Vol. 38, No.
5level of alterations in gene products, synapses, cells,
andcircuits, and then, in a bottom-up manner, map these
dis-coveries to the specific behavioral deficits
characterizinghuman neuropsychiatric conditions. Here, we focus on
thecircuits mediating reward behavior, which underlies manyof the
symptoms of human depression, such as anhedoniaand aberrant
reward-associated perception and memory.We also highlight how this
excitatory synapse hypothesis ofdepression offers a new framework
with which to approachthe treatment of patients with
depression.
The etiology of depressionDespite its high incidence and its
socioeconomic impact, thecauses of depression remain poorly
understood. Depression
Box 1. The serotonin hypothesis of depression
The monoamine neurotransmitter serotonin
(5-hydroxytryptamine,5-HT) is synthesized by neurons in the DR
nucleus. These neuronsintegrate inputs from multiple brain regions,
including the NAc,amygdala, LHb, and PFC, and send projections
throughout the brain,including to the hippocampus, PFC, substantia
nigra, and NAc.
Chance observations of mood-altering compounds more than50 years
ago led to the first coherent theory of depression andopened the
door for current first-line treatments. Evidence that theseagents
alter the concentration of monoamine neurotransmitters, suchas
serotonin, dopamine, and norepinephrine (e.g., [136]), led to
thehypothesis that depression is caused by a deficiency of
monoamines[137139]. Given that the pharmacological profile of many
AD drugs ismore consistent with changes in serotonin levels than of
othermonoamine neurotransmitters, it is now more common to speak of
aserotonin hypothesis of depression, although inhibitors of
norepi-nephrine uptake are also effective ADs, including the
tricyclics. Moststatements of the serotonin hypothesis fail to
offer mechanisticexplanations; nevertheless, this theory became a
foundation forresearch in biological psychiatry, and the central
dogma in the field ofmajor depression for many decades.
Although deficits in serotonin levels or release are a
centralprediction of this hypothesis, the relation between human
depression
and the levels of serotonin or its metabolite
5-hydroxyindoleaceticacid (5-HIAA) remains unclear, with early
enthusiasm giving way tomixed results [140]. Experimental
manipulations of serotonin levels in
280in response to stress [11].McEwen, Sapolsky, and others
emphasized the impor-
tance of allostatic overload (see Glossary) as an explana-tion
for many chronic illnesses of modern human life,including
depression [12,13]. These stressors may bephysical or psychosocial,
the latter including low self-esteem, loneliness, deficient social
skills, excessive anxi-ety, rumination, and negative thinking. All
stressorsactivate the sympathetic nervous system and the
hypo-thalamuspituitaryadrenal (HPA) axis, causing eleva-tion of
glucocorticoids (GC) and other stress hormones.Normally, the
physiological stress response is self-termi-nating, due to negative
feedback, directly via the hypo-thalamus and pituitary and
indirectly via several brain
humans by depleting or enhancing the precursor for its
synthesis,tryptophan, also remain inconclusive [141144]. In
general, acutemanipulation of tryptophan levels is more likely to
affect mood inpatients who are depressed than in otherwise healthy
individuals,perhaps because it impairs the beneficial actions of
their SSRIs.
One prediction of this hypothesis is that elevation of
serotoninlevels would relieve the symptoms of depression, and
testing thisprediction led directly to the development of SSRIs,
which produce arapid elevation of extracellular serotonin
concentration [145]. Withfewer adverse effects than the
less-specific tricyclics, SSRIs wereprescribed to tens of millions
during their first decade.
SSRI-induced elevation of serotonin increases activation of
seroto-nin receptors, of which there are 14 subtypes, each having a
uniquepattern of expression and localization. Alterations in a
singlepopulation, or subpopulation, of serotonin receptors might
also beresponsible for the symptoms of depression, rather than a
globaldysfunction of the neurotransmitter system, but evidence of
suchchanges remains inconclusive [146148].
Fifty years after the initial observations, considerable debate
aboutthe validity of the serotonin hypothesis remains, with only
incon-sistent and inconclusive evidence supporting it. It is
unlikely thatdepression is caused by a simple decrease in serotonin
synthesis,
release, or receptor expression. Nevertheless, there is clear
evidencethat elevated levels of monoamines can relieve the symptoms
ofdepression.
-
areas enriched in glucocorticoid receptors (GRs), includ-ing the
PFC and hippocampus.
A subset of patients with depression display abnormal
Box 2. The neurotrophin hypothesis of depression
Depression has been hypothesized to result when
environmentalfactors, chronic stress, and genetic susceptibility
interact to impairneurotrophin signaling [15,98,149]. The
consequences of inadequateneurotrophin signaling that might
contribute to the genesis ofdepression include impaired
neurogenesis in the dentate gyrus,atrophy of distal dendrites, and
impaired neuronal plasticity. It hasbeen further postulated that
ADs alleviate the symptoms of depres-sion by reversing or blocking
this effect, so as to restore neurotrophinsignaling. Given their
predominance in the neocortex and hippocam-pus, the most data
concern BDNF and its receptor, TrkB [150,151].
This hypothesis predicts that BDNF signaling is decreased
inpatients with depression and restored with successful AD
treatment,and there is some evidence of decreased BDNF-TrkB
signaling inhuman depression. First, serum BDNF levels are
decreased in patientswith depression [152] and recover with AD
treatment [153]. Addition-ally, BDNF and TrkB mRNA levels are
decreased in postmortem tissuefrom suicide victims [154]. Patients
treated with ADs have a higherlevel of BDNF compared with untreated
patients, specifically in thedentate gyrus, hilus, and
supragranular regions of the hippocampus[155], and increased
hippocampal neurogenesis [156]. Furthermore, apolymorphism
(Val66Met) in the BDNF gene is correlated with variousaspects of
depression and AD action (e.g., [157,158]), includingreduced
hippocampal volume, depression, and suicidality [159161].
The hypothesis also predicts that impairing BDNF signaling
shouldinduce a depressive-like phenotype and interfere with AD
responsesin animal models. Some mice with decreased BDNFTrkB
signalingdisplay a depression-like phenotype, including decreased
neuralproliferation in the dentate gyrus [94] and reduced dendritic
spine
Feature ReviewHPA axis activity, resulting in increased basal
levels ofGCs and a blunted circadian rhythm [14]. GCs
regulateneuronal survival, excitability, proliferation, and
metabo-lism, and allostatic overload may promote depression
byimpairing these processes [15]. Given their role in
negativefeedback, a dysfunction of GRs in areas such as the
hippo-campus can cause HPA dysregulation and failure to limitthe
stress response [16]. Indeed, some patients with de-pression
display an inability to suppress the axis in re-sponse to a
challenge [17]. However, HPA challenges lacksensitivity and
specificity as a diagnostic biomarker. In-terestingly, patients
treated chronically with corticoste-roids and patients with
Cushings disease, bothhypercortisolemic states, are more likely to
have depres-sion and experience a range of depression-related
cognitiveand memory deficits [18,19].
The structure of the depressed brain is different fromthe
healthy brain, likely representing one visible manifes-tation of
pathophysiology. Postmortem studies of suicidecompleters and
patients with severe depression haverevealed a reduction in the
volume of the PFC and hippo-campus, regions thought to have a role
in the cognitiveaspects of depression [20]. An impairment of
normal, on-going neurogenesis in the dentate gyrus of the
hippocam-pus, as observed in several models of chronic stress
[21],and atrophy of dendrites [22] might underlie this decreasein
hippocampal volume. Successful AD treatment reversesthese decreases
in hippocampal volume (i.e., [23]). Asreviewed elsewhere, the size
of other brain regions in-volved in regulation of reward and
emotion may also beaffected in patients with depression, including
the amyg-dala [24] and striatum [25].
density in CA1 cells [162], as well as reduced responses to
acute ADs[163]. By contrast, heterozygous BDNF-knockout mice do not
differfrom wild types in anxiety and behavioral despair measures in
some[164,165], but not all [166], studies. Monteggia et al.
reported that onlyfemale conditional forebrain BDNF-knockout mice
had a depressedphenotype and failed to respond acutely to ADs
[167]. Pyramidal cellsin the PFC of transgenic mice with the BDNF
Met allele knocked indisplay an impairment of synaptic plasticity,
but no change inbaseline synaptic function [168]. Unfortunately,
depression-relatedbehavioral assays with construct and face
validity, such as thesucrose preference and novelty suppressed
feeding tests, have notyet been tested in these mice.
Such experiments are complicated for two reasons. First,
BDNFTrkB signaling is crucial for brain development, rendering
interpreta-tion of results from knockout animals difficult. Second,
BDNFTrkBsignaling does not exert the same actions in all brain
regions. In thehippocampus and cortex, BDNFTrkB signaling promotes
resilienceto stress, whereas in the NAc BDNF promotes
susceptibility [38]. Forexample, disrupted BDNF signaling in the
NAc renders mice moreresistant to chronic social defeat [169].
Altogether, it appears that the neurotrophin hypothesis of
depres-sion is incomplete. In addition to the conflicting data in
the literature,there is no established mechanism linking serotonin
elevation tosubsequent increases in BDNF transcription and,
therefore, noexplanation as to how ADs, such as SSRIs, activate
this pathway.Nevertheless, these findings highlight the possibility
that changes inneuronal strength and plasticity underlie depression
and the action ofADs.
Trends in Neurosciences May 2015, Vol. 38, No. 5Changes in
excitatory synapses in depressionA common element linking stress,
serotonin, and neuro-trophins is their effects on excitatory
synaptic transmis-sion [26]. In preclinical studies, there is
increasingevidence that chronic stress exerts deleterious effects
onexcitatory synaptic structure and function in multiplebrain
regions associated with cognitive and emotionalcontrol of reward
behaviors that resemble those seen inhuman depression. Conversely,
serotonin and neurotro-phins exert an opposing action, generally
promoting excit-atory synaptic transmission in the same brain
regions.Many symptoms of depression seem to result from a
dys-function in the valuation of stimuli, with decreases inpositive
valuation (i.e., anhedonia) occurring in parallelwith increases in
negative valuation (disappointment, fear,or expectation of
punishment). Changes in the strength ofvarious excitatory synapses
in the distinct circuits medi-ating both of these processes have
been described.
Nucleus accumbensThe NAc is critical for integrating cortical
and hippocam-pal inputs and regulating the firing of neurons in
theventral tegmental area (VTA) [27], thereby influencingthe
motivation to seek rewarding stimuli [28], as well asmotor
behavior. Lim et al. [29] made a particularly signifi-cant advance
in our understanding of the neurobiology ofdepression with their
study of the effects of chronic stresson excitatory synapses in the
NAc (Figure 1). They ob-served that excitatory synapses in medium
spiny neurons(MSNs) in the NAc that express the D1 dopamine
receptor
281
-
(D1R) displayed a selective decrease in AMPA
receptor(AMPAR)-mediated excitation after 5 days of chronic
re-straint stress. The decrease in excitation occurred in par-allel
with anhedonia in the sucrose preference test anddepressive-like
changes in the tail suspension and forcedswim tests. Given that
D1R-expressing MSNs promoteactivation of dopaminergic cells [30],
decreased excitationof D1R cells should lower dopamine release, a
key regula-tor of reward-seeking and motivated behavior.
Experimental manipulations that decreased AMPAR-mediated
excitation in D1R-expressing cells mimicked thestress-induced
behavioral changes in unstressed animals,and manipulations that
prevented stress-induceddecreases in AMPAR-mediated excitation
blocked somebehavioral changes (sucrose preference test) in
stressedanimals [29]. Interestingly, other behaviors that are
widely
in the electrophysiological responses of dopaminergic VTAneurons
in chronic stress models remain controversial. Inone study,
optogenetic activation of dopamine-releasingVTA neurons relieved
depression-like symptoms in chron-ically stressed mice and,
conversely, inhibition of VTAneurons triggered a depression-like
behavioral phenotype[34]. Thus, the decrease in the ability of
cortical andhippocampal inputs to excite D1R cells in the NAc
afterchronic stress, described above, could underlie the
reducedfiring of VTA neurons [35,36], reduced dopamine release[37],
and the loss of the rewarding properties of variousstimuli in these
models. Changes in synaptic strengthwithin the VTA itself could
also contribute [34]. We predictthat restoration of normal behavior
by ADs should beaccompanied by a restoration of synaptic strength,
but thishas not yet been tested. However, other studies report
that
00
80
60
40
Su
ine
reco
r (NM
Feature Review Trends in Neurosciences May 2015, Vol. 38, No.
5assayed in depression studies, such as the tail suspensiontest and
the forced swim test, were not rescued by pre-venting AMPAR
downregulation in the NAc. The authorsconclude that the
stress-induced decrease in excitation issufficient and necessary
for many behavioral changes thatresemble human depression symptoms,
specifically anhe-donia, highlighting the central importance of
these synap-tic circuits to the genesis of anhedonia. The source of
theaxons forming these excitatory synapses was not identi-fied, but
is likely to include afferents from the hippocam-pus, PFC, and
amygdala. In addition to these postsynapticchanges in excitatory
synaptic strength, decreases in thefrequency of miniature
excitatory postsynaptic currents(mEPSCs), indicative of presynaptic
changes in releaseprobability, have also been reported in D1R
MSNs[31,32]. Accompanying these physiological changes, mod-est
increases in the density of stubby dendritic spines areobserved in
susceptible mice subjected to chronic socialdefeat [31,33], but the
identity of the MSNs was notdetermined.
Ventral tegmental areaThe cell bodies of dopamine-releasing
cells enervating theforebrain are located in the VTA, intermingled
with apopulation of local GABAergic interneurons, both of
whichreceive input from NAc MSNs and the PFC [27]. Changes
Pref
eren
ce (%
)
1
AMPA
:NM
D ra
o
6
4
2
Control Stressed
70 mV
+40 mV
NAc D1RMSN
(B)(A)
ControlStressed
*
Figure 1. Stress-induced internalization of AMPA receptors
(AMPARs) in D1 dopam
underlies some stress-induced depression-like behavioral
changes. (A) Whole-cell
neurons (MSNs) at 70 mV and +40 mV for analysis of AMPAR- and
NMDA receptoChronic stress decreased the AMPAR component, but not
the NMDAR component. (B,C
AMPAR internalization prevented the stress-induced loss of
sucrose preference (B),
permission, from [29]. Abbreviation: n.s., not significant.
282VTA discharge is increased in chronic stress models [3840]
and that optogenetic activation of VTA neurons pro-motes
depression-like behavior [41]. Given that: (i) drugsthat elevate
dopamine, such as cocaine, are not pro-depres-sive; (ii)
optogenetic stimulation of the PFC exerts anti-depressive effects
[42,43]; and (iii) optogenetic activation ofD1R MSNs promotes
resilience to social stress-induceddepression [32], it is unclear
how the observed increasesin VTA firing are generated and why they
should be pro-depressive. Further work is needed to reconcile
thesedifferences, perhaps by identifying subpopulations ofinputs,
synapses, or neurons within the NAc.
Prefrontal cortex[There are many subdivisions of the PFC
(infralimbic,prelimbic, orbital, dorsolateral, and ventromedial)
and,for simplicity, we omit any distinction of these regions.]The
PFC is an important site at which cognitive evalua-tions, such as
the controllability of a stressor [44] or thepleasantness of a
stimulus [45], can influence affect andreward. Patients with
depression display evidence of re-duced activity in the PFC and
SSRI treatment restoresnormal activity levels [23,46]. In animal
models, chronicstress results in atrophy of distal dendrites of
pyramidalcells in the PFC and loss of dendritic spines [47,48].
Yuenet al. [49] reported that 7 days of chronic restraint
stress
Tim
e im
mob
ile (s
)
100
200
Stress Stress
crose preference Forced swimn.s.
(C)
ControlControl pepde
Acve pepde
Untransfected
ControlControl pepde
Acve pepde
Untransfected
* * *
TRENDS in Neurosciences
receptor (D1R)-expressing medium spiny neurons in the nucleus
accumbens (NAc)
rding of evoked excitatory synaptic currents from D1R-expressing
medium spiny
DAR)-mediated components in slices from control and chronically
stressed mice.) Transfection of D1R-expressing cells with a peptide
that prevents stress-induced
but not stress-induced immobility in the forced swim test (C).
Modified, with
-
produced a decrease in synaptic excitation in layer Vpyramidal
cells in the PFC. Both AMPAR- and NMDAreceptor (NMDAR) components
of the EPSP were equallyaffected, unlike in the NAc [29] and
hippocampus (seebelow), and levels of AMPA A1 (GluA1) and NMDA
N1(GluN1) glutamate receptor subunit proteins were down-regulated
in parallel (Figure 2). The decreased expressionof GluA1 subunits
was mediated by ubiquitination andproteosomal degradation. In
addition to this postsynapticmechanism, there may also have been a
decrease in pre-synaptic release probability (decreases in mEPSC
frequen-cy, albeit no change in the paired-pulse ratio of
evokedEPSPs). No change in postsynaptic density protein 95(PSD95)
expression was detected, leaving uncertain thequestion of whether
changes in synapse number and pre-synaptic function accompany the
observed postsynapticchanges. Yuen et al. also observed no change
in GluA1function or expression in the hippocampus with 7 days
ofchronic restraint stress, a time at which GluA1 and GluN1are
decreased in PFC, suggesting that the PFC is moresusceptible to
stress. Consistent with the decrease inexcitation, expression of
several activity-dependent genesis decreased in the PFC of humans
with depression and inrodent models [42].
Activation of serotonin 2A receptors (5-HT2AR) triggersa rapid
increase in the frequency of spontaneous glutama-tergic excitatory
postsynaptic responses in pyramidal cellsin the PFC that is
mediated by the excitation of a subset of
pyramidal cells in layer VVI, while evoked EPSCs aredepressed
simultaneously [5052]. The effect of serotoninon mEPSC frequency is
diminished after chronic stress[53], although the authors failed to
report whether there isany change in the basal frequency or
amplitude after stressor whether serotonin is less effective at
exciting layer VVIcells. One potential explanation is that the
effects of sero-tonin are weaker because the intracortical
excitatory syn-apses formed by the deep layer cells are weakened
bystress, although this has not been tested.
Lateral habenulaThe lateral habenula (LHb) has received
increased atten-tion in the context of depression because of
behavioralstudies indicating that it signals negative reward
(i.e.,disappointment) [54,55]. The LHb forms a
glutamatergicmonosynaptic excitatory projection directly to both
dopa-minergic neurons in the VTA and serotonergic neurons inthe
dorsal raphe (DR), as well to the mesopontine rostro-medial
tegmental nucleus (RMTg), which then sends sub-stantial GABAergic
projections to the VTA and DR[56,57]. Stimulation of the LHb
inhibits discharge ofVTA neurons [58] and also DR cells. When
animals per-form tasks with various rewarding, neutral, or
punishingstimuli, neurons in the LHb are excited by both the
absenceof an expected reward or the presence of a punishment,
andthey are inhibited by the rewarding stimulus, especiallywhen the
stimuli are unpredictable [59]. Thus, induction of
5
nd
DAR
s (o
s of
Feature Review Trends in Neurosciences May 2015, Vol. 38, No.
5AMPA
resp
onse
am
plitu
de
Smulaon strength
Control
Stress
(A)
AMPA
resp
onse
am
plitu
de
Cont Stress
Total Surface
GluA1
GluN1
Acn
(D)(C)
300
250
200
150
100
50
5 6 7 8 9
***
#
300
250
200
150
100
50ControlStress
ControlStress
9V
8V
7V
Figure 2. Stress-induced internalization of AMPA and NMDA
receptors (AMPARs a
degradation. AMPAR-mediated [(A) 70 mV, representative currents
at right] and NM
response to a range of stimulation intensities in slices from
unstressed control rat
unpredictable stress (filled square). Stress depressed both
components regardlesplasma membrane surface insertion of glutamate
A1 (GluA1) and GluN1 receptor subuni
in AMPAR-mediated synaptic currents in response to chronic
stress, but had no effe
permission, from [49].NM
DA re
spon
se a
mpl
itude
Smulaon strength
Control
Stress
(B)
Smulaon strength
Prot
eoso
me
inhi
bito
rCo
ntro
l
Control Stress
6# *
* *
# ** *
7 8 9
300
250
200
150
100
50
5 6 7 8 9
TRENDS in Neurosciences
NMDARs) in the prefrontal cortex is mediated by ubiquitination
and proteosomal
-mediated [(B) +60 mV] excitatory currents recorded from layer V
pyramidal cells in
pen circle) and rats subjected to chronic restraint stress
(filled triangle) or chronic
stimulation intensity. (C) Chronic restraint stress decreased
both expression andts. (D) Pharmacological inhibition of
proteosomal degradation prevented decreases
ct in unstressed animals. Representative currents shown at
right. Modified, with
283
-
LHb discharge by negative reward would inhibit bothdopamine and
serotonin secretion.
In the learned helplessness model, LHb neurons dis-played an
increased frequency of mEPSCs compared withnave controls with no
change in their mean amplitude,reflecting an increased probability
of glutamate releasefrom the nerve terminals of some population of
presynapticneurons [60]. Consistent with this increased excitation,
thespontaneous action potential discharge rate of LHb neu-rons was
significantly higher after learned helplessness.Thus, these changes
could suggest a physiological basis forexcessive disappointment or
negative thinking in depres-sion. By contrast, patients with
depression subjected toacute tryptophan depletion to induce
depressive symptomsdisplayed significant decreases in
activity-dependent posi-tron emission tomography (PET) signals in
the LHb thatwere closely correlated with the occurrence and
severity ofthe depressive symptoms [61].
AmygdalaThe amygdala is critical for learning to fear
aversivestimuli and learning that previously aversive stimuli areno
longer dangerous [62]. Unlike the hippocampus, theamygdala displays
increases in volume in patients withdepression [24] and is
hyperactive [63]. Unlike the hippo-campus and PFC, chronic stress
induces dendritic hyper-trophy in the amygdala [64]. Relatively
little is knownabout changes in synaptic function to, from, and
withinthe amygdala in chronic stress models, but
optogeneticactivation of amygdala inputs to the ventral
hippocampuscan impair normal social behaviors [65].
HippocampusChronic stress induces changes in synaptic function
thatoccur in parallel with the atrophy of distal apical
dendriticbranches in pyramidal cells and decreases in the size
andnumber of dendritic spines [66,67]. While stress has re-peatedly
been shown to affect excitatory synapses in thehippocampus,
published results are somewhat conflicting.At Schaffer collateral
(SC) synapses onto CA1 cells, chronicstress is reported to have no
effect on basal synapticstrength, although it does impair long-term
potentiation(LTP), decreases GluA1 mRNA [6870], and
enhancessynaptic currents mediated by NMDARs, while
leavingAMPAR-mediated excitation unaltered in area CA3 [71].
One factor that could reconcile these discrepancies is
thedendritic location of the synapses. Stress-induced changeshave
recently been described in synaptic function at thesynapses in
distal apical dendrites of CA1 pyramidal cellsformed by
temporoammonic (TA) inputs from entorhinalcortex [72] (Figure 3).
The authors observed that 36 weeksof chronic unpredictable stress
(CUS), which is sufficient toproduce depression-like behavior in
the sucrose preferencetest and other behavioral assays, resulted in
a 50% de-crease in AMPAR-mediated excitation at TA-CA1 synap-ses.
NMDAR-mediated excitation at TA-CA1 synapses wasunaffected, as was
AMPAR-mediated excitation at neigh-boring SC-CA1 synapses.
Accompanying the decreased
Feature Reviewexcitation was a corresponding layer-specific
decrease inthe expression of GluA1 and PSD95 proteins. No changesin
the levels of GluA2 or GluN1 proteins were detected.
284This synaptic pathology had deleterious behavioral
con-sequences, as shown by the ability of CUS to disrupt long-term
memory consolidation in a spatially cued Morriswater maze task, a
function of TA-CA1 synapses [73]. Fur-ther strengthening the
relation between this synapticpathology and the behavioral
alterations produced byCUS, it was observed that changes in both
AMPAR-medi-ated excitation and GluA1 protein levels were restored
tonormal levels in stressed animals treated chronically, butnot
acutely, with fluoxetine, just like the restoration ofnormal reward
behavior.
Differences in the ability of allostatic load to
affectexcitatory synaptic function may have a role in the
deter-mination of susceptibility to becoming depressed. Schmidtet
al. [70] examined the difference between mice that werevulnerable
to behavioral changes after chronic social stressand those that
were resilient. Vulnerable mice exhibited asignificant decrease in
GluA1 and increase in GluA2 sub-units in area CA1, compared with
resilient mice. Theauthors further examined genetic polymorphisms
in genesencoding GluA1 subunits and found a SNP that correlatedwith
vulnerability to stress. How this compares to humanGluA1 gene SNPs
was not described, but this evidenceconverges with human data
implicating AMPARs [74,75].
It has also been observed that chronic stress quantita-tively
and qualitatively changes the way TA-CA1 excitato-ry synapses
respond to serotonergic stimulation[76]. Whereas activation of
postsynaptic 5-HT1BRs pro-duces a doubling of AMPAR-mediated
excitation in controlanimals that recovers within ca. 30 min of
washing out theagonist, activation of 5-HT1BRs in chronically
stressedanimals produces a potentiation that is both
significantlygreater in magnitude and more persistent (>12 h)
afterremoval of the agonist (Figure 4). Normal transientresponses
to 5-HT1BR activation are restored in CUSanimals administered
fluoxetine chronically, but notacutely. The molecular changes in
the signaling pathwaysthat underlie 5-HT1BR-induced potentiation
that underliethis effect have not yet been determined, but they
must beconfined to excitatory synapses in the postsynaptic
cell,where this potentiation is induced and expressed, to ac-count
for the stress-induced changes observed.
Not only do chronic stress models produce changes
inglutamatergic receptor function and expression, but thesechanges
may also be sufficient to cause changes in beha-viors related to
depression. For example, Chourbaji et al.[77] found that knocking
out the GluA1 gene globallyresulted in a depression-like phenotype
in the learnedhelplessness test. Similarly, it has been reported
that micein which the GluA1 gene is mutated so that it can no
longerbe phosphorylated by calcium/calmodulin-dependent(CaM) kinase
display a depression-like phenotype in thesucrose preference and
novelty suppressed feeding tests,but not in the tail suspension
test [76]. Together, thesedata make a strong argument that
disruption of hippocam-pal glutamatergic transmission, specifically
AMPAR func-tion, can accompany depression-like behavioral
changes.
Trends in Neurosciences May 2015, Vol. 38, No. 5Human
studiesAlthough less extensive than the literature on serotoninand
its receptors, there is some evidence for changes in
-
Imipramine
100
200
Syna
pc
stre
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(% c
ontr
ol)
150
50
250
300
Time (min)0 50 100
+ 5-HT1B R antagonist
Control
Before
+ 5-HT1B Ragonist
5-HT1BRagonist
Unstressed control
Stressed rats
100
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300
Syna
pc
stre
ngth
(% c
ontr
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Time (min)0 20 40 60 80 100 120 140
(B)(A) (C)
TRENDS in Neurosciences
Figure 4. Serotonin causes a serotonin 1B receptor
(5-HT1BR)-dependent potentiation of temporoammonic (TA)CA1 synapses
and this potentiation is altered by chronic
stress. (A) Field excitatory postsynaptic potentials (fEPSPs)
are recorded in stratum lacunosum moleculare in response to
stimulation of the TA pathway during application
of the tricyclic antidepressant imipramine in control saline
(black) or saline containing the 5-HT1BR antagonist isamoltane.
Elevation of endogenous serotonin produces a
doubling of synaptic strength. (B) Activation of 5-HT1BRs with
the selective agonist anpirtoline promotes action potential
discharge in CA1 cells. (C) Anpirtoline produces a
robust and reversible potentiation of TACA1 excitatory
postsynaptic currents in slices from unstressed control animals,
but produces an enhanced and persistent
potentiation in slices from rats subjected to chronic
unpredictable stress. Modified, with permission, from [76].
*
Control CUS Stress +AD
GluA
1 ex
pres
sion
0
25
50
75
100
125
0
1
2
3
4
5
6
7
AMPA
:NM
DA ra
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**
1 mV1 ms
Control Stre ss Stress + AD
0
0.1
0.2
0.3
0 0.1 0.2 0.3 0.4 0.5
AMPA
resp
onse
am
plitu
de
Smulaon strength
Stress
Control
(A)
(C)(B)
TRENDS in Neurosciences
Figure 3. Stress decreases AMPA receptor (AMPAR)-mediated
excitation and glutamate A1 (GluA1) expression at temporoammonic
(TA)CA1 cell synapses and chronic
fluoxetine reverses these effects. (A) Field excitatory
postsynaptic potentials (fEPSPs) are recorded in stratum lacunosum
moleculare in response to stimulation of the TA
pathway in Mg2+-free saline, allowing dissection of AMPAR- and
NMDA receptor (NMDAR)-mediated components. AMPAR-mediated
transmission was reduced over a
range of stimulation intensities after chronic unpredictable
stress (CUS; red) compared with unstressed rats (blue).
Quantification of AMPA:NMDA ratios (B) and GluA1
protein (C) reveals that the selective decrease in
AMPAR-mediated transmission was due to decreased GluA1 expression.
Administration of fluoxetine (antidepressant; AD)
for 3 weeks to stressed rats restored both AMPA:NMDA ratios and
GluA1 expression. Modified, with permission, from [72].
Feature Review Trends in Neurosciences May 2015, Vol. 38, No.
5
285
-
glutamatergic function in patients with depression(Table 1),
much of it mixed. Plasma levels of glutamateare decreased in some
studies [78,79], but not others [80]. Aconsiderable difficulty in
studies of this type is that gluta-mate is present in a large
metabolic pool, rendering itimpossible to know what fraction of the
measured gluta-mate is synaptic in origin. Postmortem studies
revealeddecreases in multiple glutamate receptor subunits
inpatients with depression, including the GluA1 subunit[81,82], as
well as decreased AMPAR binding in the stria-tum of suicide
completers [74,75]. Hopefully, reliable bio-markers can be found
with which to more directly assayglutamatergic function in patients
with depression.
Formal statement of the excitatory synapse hypothesis1. Major
depression is caused by a weakening of specific
subsets of excitatory synapses in multiple brain regionsthat are
critical in the determination of affect andreward. Chronic
hyperactivity of the HPA axis inresponse to excessive stress, known
to be an importantallostatic risk factor in the gene environmental
axisdetermining susceptibility to depression, is one poten-tial
mediator of these changes. High levels of GRs incells in these
regions contribute to their vulnerability.
2. Many of the characteristic changes in behavior thatdefine the
symptomatology of human depression, suchas anhedonia and depressed
mood, result because
depression, such as sleep, sex drive, sociality, workingmemory,
and attention, are similarly affected.
3. Restoration of excitatory synaptic strength is thecritical
action of effective antidepressants, includingboth conventional
agents, such as SSRIs and ECT, andnewer compounds, such as
ketamine.
Several authors have highlighted stress-induced
patho-physiological changes in reward circuits as the
biologicalunderpinning of anhedonia and other symptoms of
depres-sion [8385]. There is a strong correlation between
anhe-donia and suicide [86,87]. Indeed, anhedonia has beenfound to
be a more significant predictor of imminent suicidethan any other
psychiatric variable [88]. Social anhedonia(e.g., loss of interest
in social interaction) appears especial-ly predictive of suicidal
ideation [87]. We can predict howchanges in excitatory synapses in
regions such as thehippocampus and PFC might interact with reward
circuitsin the corticomesolimbic system to change affective
beha-viors and produce a depression-like behavioral
phenotype(Figure 5).
One important target of outputs from both the hippo-campus and
PFC is the NAc, and activation of either brainregion is positively
correlated with NAc activity (e.g., [89]).One important target of
the NAc is the VTA. Numerousstudies have shown that increased
dopamine release iscritical for appetitive motivational processes,
such as ini-
ing
alle
t in
DNF
corr
C i
ptominbfie
vera
ith
ing
late
ess
in ippo
s inract
g s
ine bol
moedo
Feature Review Trends in Neurosciences May 2015, Vol. 38, No.
5impaired excitatory synaptic transmission leads toreduced activity
in the corticomesolimbic rewardcircuitry. Other circuits that are
important in themediation of other behaviors that are altered
in
Table 1. Summary of depression related changes in humans
Refs Protein or gene Major finding
Proteins and genes
[170] NMDAR Abnormal bind
[171] 5HTT gene Promoter short
[172] BDNF Val66Met varian
[173] BDNF (review) Lower serum B
[174] 5-HT1AR (review) C(-1019)G SNP
[175] mGluR5 Decreased in PF
[176] Multiple synaptic proteins, 5-HTRs Decreased
syna5-hydroxytryptahippocampal su
In vivo PET findings in patients with depression
[175] mGluR5 Reduction in se
[177] 5-HT1AR (review) Mixed results, w
[197] 5-HT1BR Decreased bind
[179] 5-HT2R Reduction corre
[180] 5-HTT (review) Mixed results: l
[181] MAO type A Greater bindingstriatum, and h
Metabolism and activity (fMRI)
[182] N/A Hypoactive areastructures hype
[183] N/A Disrupted restin
[184] N/A Increased baseldecreased meta
[185] N/A Subgenual ACCfeedback in anh[46] N/A Successful SSRI
tredorsal ACC
[186] N/A Reduced activation
286tiation of behavior, exertion of effort, sustained task
en-gagement, and instrumental learning [90], precisely thebehaviors
that are disturbed in depression. MSNs in theNAc are GABAergic and
the D1R-expressing subset of
in brains of suicide completers
le variant promotes depression and suicidality after early life
stress
teracts with stress to promote depression
in patients with depression, normalized with AD treatment
elates with MDD, suicidality, and decreased response to
SSRIs
n unmedicated depressed postmortem samples
somal-associated protein, 25kDa (SNAP25), GLUR1, GLUR3;
increasede (serotonin) receptor 2C (HTR2C), decreased HTR4 and HTR7
inlds of patients with depression
l regions, including hippocampus and PFC
clear trend for decrease in many brain areas
in ventral striatum and pallidum
s with ECT effect
binding or no effect
many areas, including PFC, anterior cingulate cortex (ACC),
ventralcampus
clude frontal and temporal cortices; select subcortical and
limbicive (meta-analysis)
tate interhemispheral coherence
metabolism of orbitofrontal cortex, amygdala, posterior
cingulate;ism subgenual ACC and dorsal PFC
re active, dorsal ACC less active in response to
reward-relatednic individuals
atment reverses metabolism deficits in dorsal PFC, medial PFC,
and of temporal and occipital cortices during emotional task
-
sse
luta
mP
1
trans
d) to
latio
e NA
ase
e ro
essio
sulti
do
imul
, an
,70,7Normal(A) Depre
GABAKey: g
NAc
VTA VTA
LHb
RMTg
Hippo mPFC Hippo
3
(B)
Figure 5. The hypothesized impact of stress-induced changes in
excitatory synaptic
The hippocampus and prefrontal cortex (PFC) send glutamatergic
projections (re
expressing GABAergic medium spiny neurons (MSNs). These cells
inhibit a popu
inhibitory synapses (blue) onto dopaminergic VTA cells (green)
projecting back to th
cells, thereby disinhibiting VTA dopaminergic cells and
promoting dopamine rele
glutamatergic cells in the lateral habenula (LHb) project to
GABAergic neurons in th
VTA. Chronic stress induces anhedonia and other reward-related
symptoms of depr
on D1R MSNs. There is also a potentiation of excitatory inputs
onto LHb neurons, re
inhibition of VTA cells. These changes synergistically increase
the inhibition of VTA
therapies [selective serotonin reuptake inhibitors (SSRIs),
ketamine, deep brain st
serotonin-dependent strengthening of excitatory synapses in the
hippocampus, PFC
stimuli (C). Evidence of changes in synaptic excitation: 1 [29];
2 [4749,53,104]; 3 [69
[76]; tricyclic [189]; 7 ketamine [104]; 8, long-term
potentiation (LTP)? [42].
Feature ReviewMSNs activates dopaminergic cells by inhibiting
intrinsicVTA GABAergic cells [30]. Thus, the net effect of
activationof D1R cells in response to inputs from the
hippocampusand PFC is to promote dopamine release.
Stress-inducedweakening of excitatory synapses onto D1R cells [29]
wouldmake it harder for rewarding stimuli to trigger the
normalactivation of dopaminergic VTA neurons and the release
ofdopamine. Hence, D1R MSNs would be less effective ateliciting
positive reinforcement or motivated behavior.Similarly, weakened
excitatory synapses in the hippocam-pus and PFC would decrease the
afferent drive that theNAc receives from these regions [91] and
also diminish therelease of dopamine by reward-reinforcing stimuli
(e.g.,[37,92]). Decreased drive to the amygdala from the PFCand
hippocampus may also be important. These changesoccur in parallel
to, and are synergistic with, the increasedinhibition of VTA cells
mediated by changes in the LHbRMTg circuit, as discussed above.
It is important to note that we do not predict that
everyexcitatory synapse is affected by stress, even in the
sameregion. In the NAc, synapses on D1R cells are affected, butnot
those on D2R cells [29,32]. In the hippocampus, TA-CA1 synapses are
weakened by chronic stress, but SCsynapses are not [72]. Second,
not every stress-sensitiveexcitatory synapse responds in the same
manner. Forexample, synapses involved with positive valuation
aremore likely to be weakened by stress, whereas synapsesinvolved
in negative valuation become strengthened. Moresynapses need to be
examined to clarify these issues.Finally, the range of behaviors
that are altered in stressand depression provides clear evidence
that there arelikely to be multiple synapses that are adversely
affectedd
mate dopamine
AD treated
NAc
FC Hippo mPFC
NAc
VTA
2 6 7
8
LHb
RMTg
LHb
RMTg
4
5
TRENDS in Neurosciences
(C)
mission on the reward circuitry and the mechanisms of
antidepressant (AD) action.
the nucleus accumbens (NAc), where they excite D1 dopamine
receptor (D1R)-
n of interneurons within the ventral tegmental area (VTA) that
form GABAergic
c, hippocampus, and PFC. When the hippocampus or PFC is active,
they excite D1R
(A). There is a distinct circuit mediating responses to negative
stimuli, in which
stromedial tegmentum (RMTg), which in turn inhibit dopaminergic
neurons in the
n because of a weakening of excitatory synapses in the
hippocampus and PFC and
ng in an increase in the excitation of RMTg neurons and
subsequent increase in the
paminergic cells, thereby impairing dopamine release (B).
Effective antidepressant
ation (DBS), or electroconvulsive therapy (ECT)] can all trigger
an activity- and/or
d NAc, thereby restoring the normal release of dopamine in
response to rewarding
2,187,188]); 4 [60]); and 5 [178]). Evidence of synaptic
strengthening by ADs: 6 SSRI
Trends in Neurosciences May 2015, Vol. 38, No. 5by stress, with
no one synapse likely to be uniquely re-sponsible for generating
the depressed phenotype.
Restoration of excitatory synaptic strength within
thehippocampus and PFC, as well as restoration of thestrength of
excitatory synapses onto D1R cells, wouldrestore the ability of
rewarding stimuli to promote dopa-mine secretion. Thus, our
hypothesis predicts that anyagent or manipulation that strengthens
key stress-sensi-tive excitatory synapses in the reward system may
be aneffective AD. Indeed, optogenetic stimulation of the PFCexerts
AD-like effects in the sucrose preference and socialinteraction
tests in rodent models [42,43], equivalent to theeffects of chronic
SSRIs. Furthermore, direct optogeneticactivation of D1R MSNs
promotes resilience to socialstress-induced depression [32].
The excitatory synapse is also a place where serotoninand
brain-derived neurotrophic factortropomyosin recep-tor kinase B
(BDNFTrkB) receptor signaling converge.BDNF secretion is promoted
by glutamatergic excitation.Considerable evidence ties BDNF and
TrkB to synapse-strengthening processes, such as LTP. Application
ofBDNF also results in morphological and functionalchanges that
parallel LTP, including increased spine for-mation and higher
amplitudes and frequency of miniatureEPSCs in CA1 neurons in the
hippocampus [93]. Finally,there is considerable evidence that
BDNFTrkB signalingpromotes the generation and survival of granule
cells inthe dentate gyrus [94]. Proliferation of these cells and
theirincorporation into the hippocampal circuitry should
alsopromote activity within hippocampal circuits, thereby
pro-moting hippocampal throughput and output. Thus,BDNFTrkB
signaling is both promoted by excitation
287
-
and promotes excitation. Similarly, insufficient serotonin(Box
1) may lead to loss of on-going maintenance of synap-tic strength
(see below). Conversely, insufficient synapticstrength may weaken
the drive of neurons in the DR fromthe limbic cortices [95] and
diminish serotonin release.
Therapeutic implications of the excitatory
synapsehypothesisAlthough the development of SSRIs has improved
thetreatment of major depression, there is still considerableneed
for better therapeutic options. Can the excitatorysynapse
hypothesis account for the actions of existingtherapies and point
towards new strategies?
SSRIsOur understanding of how SSRIs relieve depressiondepends
upon understanding how serotonin affects brainfunction. Two effects
appear central to understanding thebeneficial actions of SSRIs:
promoting neurogenesis andpromoting excitatory interactions at
specific loci. There isstrong evidence that SSRIs promote the
proliferation ofprogenitor cells in the subgranular zone of the
dentategyrus, leading to the increased genesis and survival
ofdentate granule cells [96]. Given the evidence that chronicstress
impairs neurogenesis of these same cells [97], it hasbeen proposed
that restoration of neurogenesis is a criticalfactor in the AD
action of SSRIs [98], presumably byincreasing hippocampal output,
although this is rarelydiscussed.
There is also considerable evidence that serotonin reg-ulates
excitatory synaptic transmission in various brainregions through
actions at multiple serotonin receptorsubtypes. In the hippocampus,
elevation of serotonin levelswith SSRIs potentiates excitation at
both mossy fiberCA3cell synapses, via an action at 5-HT4Rs [99],
and TACA1cell synapses, via an action at 5-HT1BRs [76].
Furthermore,the ability of fluoxetine to restore normal sucrose
prefer-ence and novelty suppressed feeding behaviors is
compro-mised when 5-HT1BRs are blocked pharmacologically ordeleted
genetically, suggesting that this potentiation isrequired for the
therapeutic actions of SSRIs [76]. As dis-cussed above, serotonin
also promotes excitatory synaptictransmission in the PFC.
Ketamine and NMDAR antagonistsOne of the greatest recent
advances in our understandingof depression was the finding that
antagonists of NMDAreceptors, particularly ketamine, have rapid,
robust, andsustained (710 days) AD-like effects in humans[100,101].
Multiple studies have shown that acute admin-istration of ketamine,
at doses that are said to be lowerthan those that produce
psychotomimetic responses, pro-duces improvement in mood and
reduces depressivesymptoms, including suicidal ideation, within 12
h;these improvements persist for up to 2 weeks. Rodentstreated
acutely with ketamine exhibited an AD-like phe-notype in the forced
swim [102], novelty suppressedfeeding, and learned helplessness
tests [103]. Further-
Feature Reviewmore, ketamine restored sucrose preference and
noveltysuppressed feeding behaviors rapidly in chronicallystressed
animals [104].
288Although an area of on-going investigation, the gener-ally
accepted model of the therapeutic effect of ketamine isconsistent
with the hypothesized involvement of excitatorysynapses in
depression. The actions of ketamine can bedivided into an induction
phase of 12 h in duration,during which it is present in the brain
at sufficient con-centrations to inhibit NMDARs, and an expression
phase,in which symptoms are relieved for 12 weeks after wash-out of
the drug from the brain.
There are two hypotheses about how ketamine actsduring the
induction phase. Ketamine may exert a prefer-ential inhibition of
NMDARs on GABAergic inhibitoryinterneurons [105107]. This could be
due to differencesin subunit composition or because interneurons
are moredepolarized than are pyramidal cells, relieving ion
channelblock by Mg2+ and allowing NMDARs to contribute more totheir
overall excitation. Thus, ketamine produces a milddisinhibition of
the neuronal population, an increase inhigh-frequency oscillatory
activity in rats [108,109] andhumans [110,111], and a
neurochemically detectable surgeof glutamate release in the PFC and
NAc [105,112,113]. Co-incident with the washout of ketamine at the
end of theinduction phase, glutamate concentrations return to
nor-mal [114]. Ketamine has recently been shown to exert
anantidepressant-like action in the forced swim test in micelacking
NMDARs in a subset of GABAergic interneurons[115], which could
indicate that another population ofinterneurons is critical or that
its actions do not dependon blocking interneuron NMDARs.
Unfortunately, theauthors did not determine whether ketamine was
ableto elicit increased activity in these animals.
The alternative hypothesis states that ketamine blockson-going
activation of NMDARs mediated by spontaneoustransmitter release
[116]. This on-going activity is postu-lated to produce
constitutive suppression of signaling path-ways that promote
excitatory synaptic transmission. Byrelieving this suppression,
ketamine may promote expres-sion of several proteins that
potentiate excitatory synap-ses, including AMPARs [104,116].
Regardless of which hypothesis is true, both share
thestrengthening of excitatory synapses, persisting through-out the
expression phase, as their common effector mecha-nism. Several
activity-dependent consequences of a periodof increased network
activity have been implicated, such asactivation of the mammalian
target of rapamycin (mTOR)signaling pathway or deactivation of the
eukaryotic trans-lation elongation factor 2 (EEF2) pathway, and
rapidtranslation of proteins from pre-existing mRNAs, as wellas
induction of the immediate early gene FBJ murineosteosarcoma viral
oncogene homolog B (FosB) and itsdownstream genes. All three
mechanisms ultimately leadto direct potentiation of synapses, the
induction of synapse-related genes, and increased synthesis of
synaptic proteinswithin hours [103,116], thereby strengthening
patholog-ically weakened excitatory synapses [104]. Ketamineappears
to induce LTP-like processes, as suggested bythe finding that
ketamine triggers an increase in surfaceexpression of AMPARs [117].
Indeed, ketamine loses its
Trends in Neurosciences May 2015, Vol. 38, No. 5AD effect in the
absence of functional AMPARs[117,118]. Ketamine also promotes BDNF
synthesis andrelease, which may be required for its actions
[116].
-
Unfortunately, the adverse effects of ketamine havehindered its
clinical usefulness. Considerable effort isnow being made to
develop other inhibitors of NMDARfunction that might preserve the
rapid AD actions ofketamine without its adverse effects.
Alternatively, thehypothesis predicts that any compound that either
pro-motes LTP-like processes or promotes ketamine-likeincreases in
oscillatory activity by any other means wouldalso strengthen
excitatory transmission and exert an ADaction. Indeed, Kumar et al.
[119] have shown that rhyth-mic optogenetic activation of the PFC
exerts an AD-likeeffect in the forced swim test and increases
oscillatoryactivity throughout the mesolimbic reward circuitry,
in-cluding the VTA and NAc [119].
ScopolamineThe nonselective antagonist of muscarinic
acetylcholinereceptors, scopolamine, exerts an antidepressant
actionthat is slower than ketamine, but faster than SSRIs (ca.35
days) [120]. Similar to ketamine, scopolamineincreases signaling
via the mTOR pathway in the PFCand increases the number and size of
dendritic spines onlayer V pyramidal cells, as well as the ability
of serotonin toincrease the frequency and amplitude of spontaneous
glu-tamatergic synaptic currents [121]. These responses areprobably
triggered by a short burst of neuronal activity,as suggested by the
detection of elevated glutamatelevels with microdialysis, as seen
with ketamine. Indeed,
blocking PFC AMPARs was sufficient to prevent the abilityof
scopolamine to produce an AD-like response in the forcedswim
test.
Positive allosteric modulators of AMPARsDrugs that block AMPAR
desensitization and/or deactiva-tion are one promising way to exert
AD action by directlypotentiating excitatory synapses. The AMPAR
potentiatorLY392098, for example, exerted AD-like actions in the
tailsuspension and forced swim tests, although it did notrestore
sucrose preference after chronic stress[122,123]. In addition to
their direct effects on excitation,AMPAR potentiators increase BDNF
mRNA in the hippo-campus [124]. Finally, AMPAR potentiators may be
usefulin accelerating the therapeutic response to SSRIs [125].
Deep brain stimulationDeep brain stimulation (DBS) has attracted
considerableattention as a means to alleviate treatment-resistant
de-pression, although the mechanisms underlying its thera-peutic
effects and specific loci of action remain poorlyunderstood. In
humans, repetitive stimulation of the sub-callosal cingulate gyrus
has been shown to be therapeuticin some patients [126]. Similarly,
in preclinical models,optogenetic and electrical stimulation of the
medial PFChas an AD effect [42]. DBS of the rat PFC gray matter
alsocaused an AD-like response in the forced swim,
noveltysuppressed feeding, and sucrose preference tests [127].
Feature Review Trends in Neurosciences May 2015, Vol. 38, No.
5Box 3. Outstanding questions
How does chronic stress impair synaptic structure and
function?Changes associated with stress have been attributed to a
variety ofmediators, including corticosteroids, peptide hormones
[e.g., corti-cotrophin-releasing hormone (CRH)], opioid peptides,
monoamines(e.g., serotonin or dopamine), inflammatory cytokines,
endocanna-binoids, and neurosteroids, to name a few [190].
Glucocorticoids areby no means singly important but are likely the
best known. In oneexample, chronic administration of corticosterone
to nave rats andmice was sufficient to produce depressive-like
behavior andrecapitulate several molecular markers of chronic
stress models[191], presumably via glucocorticoid receptors (GRs).
Neuronsthroughout the cortex, hippocampus, and ventral striatum
expressGRs at high levels, rendering them vulnerable to chronic
stress. Thedownstream mediators of persistent GR activation are
unknown butultimately alter expression of synaptic proteins through
alteredsynthesis, turnover, and degradation [49]. What makes
somesynapses selectively vulnerable? Distal dendrites are
particularlysensitive to the atrophic effects of chronic stress and
contribute, atleast in part, to the localization of the altered
synaptic compositionand function [72,187]. Studies continue to
unravel new roles for allthe known mediators of stress, sometimes
with differing short- andlong-term actions, and to elucidate the
molecular mediators betweenstress and impaired synaptic
function.
How do SSRIs act in the NAc and LHb? Activation of
5-HT1BRstriggered a persistent inhibition of excitatory synaptic
transmissionin the NAc in unstressed animals [192,193]. The
hypothesis predictsthat this action of serotonin would promote, not
relieve, thesymptoms of depression. It remains to be determined
what theeffects of chronic SSRI or acute ketamine administration
are onthese synapses. Similarly, do SSRIs renormalize plastic
changes insynapses in the LHb and RMTg? This will be particularly
informative
because the direction of the depression-associated
synapticplasticity in this circuit (strengthening) appears opposite
to thatseen in the hippocampus, PFC, and NAc (weakening). Why do
SSRIs induce immediate elevation of serotonin levels [145]and rapid
potentiation of excitatory synapses [76], but a delayedtherapeutic
response? The hypothesis predicts that an immediatestrengthening of
stress-weakened synapses should relieve symp-toms rapidly. Indeed,
cocaine produces a rapid strengthening ofexcitatory synapses in the
NAc [194] and an immediate euphoricresponse. It may be that
multiple bouts of serotonin-inducedpotentiation are necessary to
render them persistent, perhaps inconjunction with slower changes
in neurotrophin signaling, for theeffects to be sustained. Only
repeated administration of cocaine, forexample, leads to a lasting
disinhibition [30] or increases in mEPSCfrequency [195] in VTA
dopamine neurons. Alternatively, SSRIsmay elicit acute actions in
other brain regions, such as theamygdala, that may oppose their
actions in reward circuits. Notenough is known about the actions of
SSRIs in mesolimbic rewardcircuits. Finally, it will be important
to determine whether ADs thataffect norepinephrine and DA levels
also produce changes in thesecircuits.
How and where does DBS work? The effects described in
somepatients offer encouragement that DBS may offer sorely
neededrelief for the patients who are most severely depressed
and/ortreatment resistant [126], but the low rate of surgical
successsuggests that we do not yet know enough about what
structures orpathways to target and perhaps what stimulus
parameters to use.Preclinical studies are likely to suggest the
best places torenormalize reward circuitry.
Can compounds be developed that retain the beneficial rapid
ADaction of ketamine without the adverse effects? Current efforts
todevelop NMDAR antagonists with unique pharmacological proper-ties
and subunit selectivity appear promising [196], although theadverse
effect profile is not yet clear. If our understanding of how
ketamine works is correct, then any drug that promotes
synchro-nized oscillatory activity in the PFC and hippocampus
should alsohave an AD action, similar to that of ketamine.
289
-
The hypothesis described here predicts that
repetitivestimulation, particularly of PFC and hippocampal inputsto
the NAc, may induce activity-dependent synaptic poten-tiation or
induce activity-dependent genes and transcrip-tion factors, similar
to ketamine. Whether and where in thebrain these processes occur
remain to be determined.Interestingly, direct stimulation of the
ventral striatalreward circuitry may be equally efficacious in
humanswith depression [128,129]. Finally, preclinical studies
havesuggested that DBS acts indirectly by promoting the re-lease of
serotonin [127].
Electroconvulsive therapyThere is a compelling overlap between
direct methods ofexciting the brains of patients with depression to
improvemood and the high-frequency stimuli that induce LTP
atexcitatory synapses within and between many of the brainareas
discussed above. Electroconvulsive therapy (ECT), inwhich a
generalized seizure is induced by delivering 20120-Hz stimulation,
is one of the oldest treatments fordepression still in use,
although typically reserved forpatients resistant to
pharmacological treatment, or wheresuch treatment is
contraindicated, such as many olderpatients.
ECT-like stimulation in rats is known to induce an LTP-like
potentiation of excitatory synapses in the dentategyrus that
persists for up to 40 days [130]. Similar toconventional LTP, this
ECT-induced potentiation is inhib-ited by an NMDAR antagonist [131]
and is accompanied byan increase in phosphorylation of ser831 of
GluA1 andS1301 of GluN2B. Changes in overall receptor
expressionwere observed in some studies [132], but not others[133].
Interestingly, ECT also promoted an NMDAR-de-pendent increase in
BDNF expression in animal models[134,135].
Concluding remarksIn conclusion, although there are many
important ques-tions that remain (Box 3), there is considerable
evidencethat dysfunction of excitatory synapses contributes to
thepathology of depression and that many effective antide-pressants
act to restore normal synaptic strength. Werecognize that the
evidence in support of the hypothesisis far from complete and that
the circuits are more complexthan we have indicated here. Our
intent in formulatingthis hypothesis is to stimulate further work
and to providea conceptual framework with which to interpret
theresults. We hope that these efforts lead to a better
under-standing of the causes of depression and thereby to
bettertherapeutic options that increase the number of patientswho
can be treated effectively and that their symptoms canbe relieved
more quickly.
AcknowledgmentsWe are grateful to Bradley Alger for teaching us
the importance of a wellformulated hypothesis. We thank our
colleagues Mary Kay Lobo, BrianMathur, Todd Gould, Robert Schwarcz,
and T. Chase Francis for theircomments on the manuscript. S.M.T.
and X.C. were supported by grantR01 MH086828, A.J.K. and A.M.V.
were supported by T32 GM008181,
Feature ReviewM.D.K. was supported by T32 NS063391, and T.A.L.
was supported byT32 NS007375.
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