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Rev Neurosci. 2011 ; 22(5): 535–549. doi:10.1515/RNS.2011.044.

Structural and synaptic plasticity in stress-related disorders

Daniel J. Christoffel, Sam A. Golden, and Scott J. Russo*
Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of
Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029-6574, USA

Abstract
Stress can have a lasting impact on the structure and function of brain circuitry that results in long-
lasting changes in the behavior of an organism. Synaptic plasticity is the mechanism by which
information is stored and maintained within individual synapses, neurons, and neuronal circuits to
guide the behavior of an organism. Although these mechanisms allow the organism to adapt to its
constantly evolving environment, not all of these adaptations are beneficial. Under prolonged
bouts of physical or psychological stress, these mechanisms become dysregulated, and the
connectivity between brain regions becomes unbalanced, resulting in pathological behaviors. In
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this review, we highlight the effects of stress on the structure and function of neurons within the
mesocorticolimbic brain systems known to regulate mood and motivation. We then discuss the
implications of these spine adaptations on neuronal activity and pathological behaviors implicated
in mood disorders. Finally, we end by discussing recent brain imaging studies in human
depression within the context of these basic findings to provide insight into the underlying
mechanisms leading to neural dysfunction in depression.

Keywords
2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA); dendritic spines;
depression; mesolimbic dopamine system; nuclear factor κB (NF-κB); synapse

Introduction
Neurons are integrative units that synthesize inputs from an array of connected neurons to
generate outputs, in the form of action potentials that result in dynamic neuronal ensembles
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(Buzsáki, 2010). To allow for this coordinated activity among neurons, they contain a
specialized structure known as the synapse, which is the focal point of information exchange
between neurons. The brain contains billions of neurons that give rise to trillions of
synapses, which are dynamic, regulated aspects of interneuronal communication capable of
maintaining a history of neuronal activity (Hebb, 1949; Yasui et al., 2005).

The synapse is principally a unidirectional point of information transmission in the brain

with a presynaptic axon terminal delivering a signal that is received and propagated by the
post-synaptic aspect. Our ability to process and incorporate information is dependent on
synaptic plasticity mechanisms (Holtmaat and Svoboda, 2009; Wilbrecht et al., 2010). A
majority of the literature has focused on the synaptic plasticity at excitatory synapses that
are present mainly on small protrusions of the dendrite called spines. Ramon y Cajal
observed spines and speculated on their function over a century ago, but it is only in the past
few decades that we have made fundamental progress in understanding how synaptic

Copyright © by Walter de Gruyter • Berlin • Boston.

*
Corresponding author: [Link]@[Link].
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adaptations relate to brain functions such as learning and memory (Shepherd, 1996; Hayashi
and Majewska, 2005; Bourne and Harris, 2007; Higley and Sabatini, 2008; Kasai et al.,
2010; Penzes et al., 2011).
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Dysregulation of synaptic plasticity has been implicated in a variety of psychiatric disorders

(Russo et al., 2009; Cruz-Martín et al., 2010; Hayashi-Takagi et al., 2010; Penzes et al.,
2010), neurological disorders (Akram et al., 2008; Bingol and Sheng, 2011), and in age-
related cognitive impairment (Dumitriu et al., 2010). Genetic mutations have been identified
that disrupt normal developmental plasticity mechanisms. Alternatively, life experience can
cause changes in synaptic connectivity that result in pathological wiring of neural circuits.
Uncovering the fundamental principles of synaptic adaptation is critical to both the
understanding of the disease state as well as the discovery of novel therapeutics. In this
review, we focus on stress-induced synaptic remodeling in animal models of depression and
anxiety disorders. We also discuss the functional relevance of these synaptic adaptations,
identify how these basic findings translate to the clinical populations, and finally how this
information might aid in developing new therapeutics.

Animal models of stress

Stress is a well-established precipitating factor in several psychiatric diseases including
major depressive disorder (MDD) and post-traumatic stress disorders (PTSDs) (Kessler,
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1997). Therefore, animal models of these disorders often use stressors to understand the
neural mechanisms underlying this form of experience-dependent behavioral plasticity
(Figure 1). There are numerous stress paradigms available and each allows us to investigate
unique aspects of stress and stress-induced behaviors providing the means to discover
universal and stimulus-specific mechanisms of plasticity. Although none of these models
recapitulate stress-related psychiatric disorders fully, they are useful tools to model specific
symptoms of these disorders.

The various stress paradigms employed rely either on acute or chronic stress. Although
acute stress paradigms have been used as expedient means to test antidepressant efficacy and
the pro- or antidepressant effect of gene knockouts and transgenics, they lack construct
validity for most stress-related disorders and have limited face and predictive validity.
Chronic stress paradigms may be more homologous to the human condition, and some of the
behavioral phenotypes induced by these models uniquely respond only to chronic
administration of antidepressants mimicking the therapeutic response in patients with MDD.

Acute models of stress

Tail suspension stress and forced swim stress are examples of acute stressors that were
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developed as tools to test the efficacy of antidepressant compounds (Porsolt et al., 1978;
Steru et al., 1985). In both models, the critical response measured is immobility, which is
believed to measure despair-like behavior. Both of these models have some success in
predicting the efficacy of antidepressant compounds in humans; however, given that
antidepressants have a rapid effect in these models, their utility in interpreting therapeutic
effects is less clear. Moreover, given the acute nature of the stressors, these models do not
mimic the pathophysiology of depressive disorders. Learned helplessness is the delivery of
an uncontrollable stressor (i.e., footshock) over one or more sessions. In a subsequent testing
condition, animals exposed to a stressor show reduced escape attempts to an escapable
stressor (Weiss and Glazer, 1975). Although this model also has some predictive validity, it
lacks face validity; the stressor produces a transient helplessness phenotype in these models
that is typically gone 72 h after the stressor. The absence of long-lasting phenotypes impairs
the utility of these models in determining long-lasting changes in neuronal morphology
relevant to chronic relapsing stress disorders.

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Chronic models of stress

Historically, various forms of chronic stress have been utilized to model depression-like
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behavior in mice, such as chronic social defeat stress (CSDS), chronic restraint stress (CRS),
and chronic unpredictable stress (CUS) followed by behavioral measures of anhedonia
(sucrose preference) or despair (forced swim test and tail suspension test) (Krishnan and
Nestler, 2010; Nestler and Hyman, 2010). Importantly, behavioral phenotypes induced by all
three of these chronic stressors have been identified that are reversible by chronic, but not
acute, antidepressant treatments (Berton et al., 2006; Tsankova et al., 2006; Schmidt and
Duman, 2010; Christiansena et al., 2011). This is an especially attractive feature compared
with models that do respond to acute antidepressant treatments, as it allows for an efficacy
comparison between novel fast-acting therapeutic interventions and the more classic slower-
acting pharmacotherapies.

The CSDS model of depression results in a robust depression-like phenotype marked by

anhedonia, anxiety, and social-avoidance behaviors (Kudryavtseva et al., 1991; Rygula et
al., 2005, 2006a,b). In this model, c57BL/6J mice are subjected to 10 once-daily bouts of
social defeat by a larger CD-1 mouse that has been screened for aggressive behavior (for
detailed protocol see, Golden et al., 2011). Following completion of the social defeats, a
majority of mice (65%) develop a constellation of depression-like symptoms and therefore
are termed ‘susceptible’, whereas a minority (35%) fail to show these symptoms and are
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termed ‘resilient’. Taken together, social avoidance exhibited by susceptible mice is

associated with a myriad of hedonic changes and weight gain, whereas both susceptible and
resilient mice show increased anxiety and corticosterone reactivity (Krishnan et al., 2007).
The behavioral syndrome induced by social defeat makes this model useful in studying
individual differences in depression- and anxiety-associated behaviors and has the
discriminative ability to distinguish animals on these behavioral domains. This feature is of
great importance owing to the dynamic range of reactions an individual can exhibit in
response to stressors, whether it is the development of a major depressive disorder, PTSD, or
resiliency to such disease states (Yehuda et al., 2006). However, a major caveat of the CSDS
model in c57BL/6J mice is that female mice are not easily defeated, and thus the model is
limited at this point to studying male responses. Regardless, the ability to study individual
responses to social stressors has become increasingly useful in modeling aspects of
depression-like behavior (Kudryavtseva et al., 1991; Koolhaas et al., 1997; Butterweck et
al., 2001; Krishnan and Nestler, 2008; Miczek et al., 2008; Rygula et al., 2008) with high
construct, face, discriminative, and predictive validity (for an more in-depth review of these
terms, see Nestler and Hyman, 2010).

CRS has been used extensively to determine the morphological, hormonal, and behavioral
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changes due to repeated stress. Typically, this model consists of restraining an animal for 1–
6 h each day in a restraint device (bag or cage) for a period of 3 weeks or more (Watanabe et
al., 1992; Radley et al., 2006). This model has been shown to produce changes in the
morphology of neurons in the hippocampus, prefrontal cortex (PFC), and amygdala (Table
1). Behaviorally, this model induces depressive-like symptoms establishing a degree of face
validity, and depending upon the behavioral measure examined following the stress (i.e.,
novelty suppressed feeding), it demonstrates predictive validity in responding only to
chronic antidepressant treatment. A disadvantage of the CRS model is that during chronic
stress, animals habituate over time and show no increase in hypothalamic-pituitary-adrenal
(HPA) axis activation. This contrasts with the clinical situation, where it is well documented
that depressed individuals show hyperactivity of the HPA axis (Carroll et al., 1976; Stetler
and Miller, 2011).

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CUS is a stress model developed to overcome stress habituation that occurs during CRS. It
has also been recently adapted to study sex differences in stress responses and thus, unlike
CSDS, is useful in studying mechanisms of depression in females (LaPlant et al., 2009). It
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involves subjecting animals to a variety of stressors (tail suspension, footshock, restraint,

cage tilt, etc.) in a semi-random or unpredictable order over the course of several days to
weeks (Papp et al., 1991). Owing to the gradual development of stress-induced behavioral
deficits, this model demonstrates construct validity and has been particularly useful in
studying anhedonic responses or loss of interest in pleasurable activities (i.e., sucrose
consumption, sex, and social interaction). Some of these behavioral deficits are long lasting
and are only reversed by chronic antidepressant treatment and thus are more relevant to
human disease.

Structural and synaptic plasticity

Stress-induced structural plasticity of dendrites and spines was first identified in
hippocampal pyramidal neurons (McEwen, 2000). Exposure to CUS was shown to induce
dendritic atrophy in hippocampal regions (Magarinos and McEwen, 1995). Subsequently,
other forms of stress, such as CRS in rats, which leads to a glucocorticoid-dependent
atrophy of dendrites on CA3 (Magarinos et al., 1997) and CA1 pyramidal neurons (Sousa et
al., 2000) demonstrated a more general effect of stress on hippocampal structural plasticity.
The effect of stress on spine density in the hippocampus is less clear. One study shows an
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increase in spines on CA3 dendrites (Sunanda et al., 1995), whereas others observed no
changes in spine density (Magarinos et al., 1996) or a decrease in spines that is reversible
with recovery (Sandi et al., 2003; Stewart et al., 2005). Additionally, an ultrastructural study
of CA1 synapses found an increase in the size of the postsynaptic density following CRS
(Donohue et al., 2006). Collectively, these studies suggest that stress alters the morphology
and, thus, the strength of hippocampal excitatory synapses, although it is not clear whether
the discrepancy in overall spine number is due to methodological differences.

Paralleling changes in the hippocampus, the PFC shows a general atrophy of dendrites and
spines in response to stress. For example, CRS has been shown to lead to dendritic atrophy
and spine loss (Wellman, 2001; Cook and Wellman, 2004; Radley and Morrison, 2005;
Goldwater et al., 2009); both of which are reversible following a period of recovery (Radley
et al., 2006; Goldwater et al., 2009). These changes are shown to occur in both the prelimbic
(PL) and infralimbic (IL) regions of the PFC. Interestingly a subpopulation of IL neurons
that project to the basolateral amygdala (BLA) seem to be resistant to these stress-induced
changes (Shansky and Morrison, 2009). Further demonstrating the circuit specific effects of
stress on neuronal remodeling, one study found a 43% increase in the dendritic arborization
of the orbital frontal cortex, an effect opposite to what is observed in other cortical neuron
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populations (Liston et al., 2009).

In the amygdala and the nucleus accumbens (NAc), subcortical limbic structures involved in
mood regulation, stress generally results in an increase in spine density. CRS results in a
hypertrophy of dendritic arborization and increased spine density in basolateral amygdala
spiny neurons (Vyas et al., 2003, 2004, 2006; Mitra et al., 2005). Recovery following stress
does not reverse these changes. Similarly, CSDS in mice increases spine density, mainly
stubby spines, on NAc mediums spiny neurons (MSNs) (Figure 2A). These new spines are
associated with generally smaller postsynaptic densities (PSDs) and an increase in the
frequency of mini-excitatory postsynaptic currents (mEPSCs), indicating a greater number
of functional glutamatergic synapses. To date, no studies have examined the effects of
CSDS on the dendritic arborization in these neurons or other forms of synaptic plasticity.
Interestingly, while neurons in the BLA and the NAc shell both undergo increases in spine
density, these two neuron types differ greatly in their molecular composition. BLA neurons

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are generally thought to be glutamatergic and pyramidal-like, whereas NAc MSNs are
GABAergic (Zahm, 2000; Sah et al., 2003). Perhaps surprisingly, spiny neurons in the
medial amygdala, which are GABAergic and morphologically more similar to NAc MSNs,
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show a decrease in spine density after acute inhibitory avoidance stress (Bennur et al.,
2007). What can account for these divergent density changes in varying neuronal types? It is
possible that NAc and BLA neurons share some common downstream mechanisms or
synaptic inputs that promote similar spine changes. Indeed the BLA projects to the NAc, and
altered functioning of the BLA may induce similar plasticity in the NAc. Additionally, the
shell of the NAc has been thought to be part of the extended amygdala (Zahm, 2000), and
both the NAc and the amygdala are projection regions of the ventral tegmental area (VTA),
which also undergoes stress-induced plasticity (Krishnan et al., 2007). Thus, future studies
mapping the connections to and from these diverse neuronal populations undergoing
synaptic plasticity will be critical to understand whether differences in synaptic morphology
observed after chronic stress are due to their synaptic inputs.

Owing to recent advances in optical technologies over the past decade, it is now possible to
perform high-throughput categorization of spines based on morphological characteristics.
Although spines appear on a morphological continuum, the gross categorizations of thin,
mushroom, and stubby spines has been useful. It has been argued that these different spine
types serve different functions. Thin and stubby spines are prevalent during development
and are considered to be immature plastic structures, whereas mushroom spines are more
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stable and have larger, stronger synapses (Harris and Kater, 1994; Petrak et al., 2005). It is
hypothesized that the stubby spine, which has a nonrestrictive neck, is strongly coupled to
the parent dendrite (Schmidt and Eilers, 2009). Changes in the percentage of these spines
may then have a greater impact on neuronal excitability than others (Noguchi et al., 2005)
(Figure 3). Interestingly, it has also been shown that stubby spines are mainly innervated by
cortical afferents in the amygdala and undergo afferent specific plasticity (Humeau et al.,
2005). In light of their differential functions, emphasis is now being placed more on the
shifts in spine types and less on the overall density. For instance, although CRS has been
shown to result in an overall spine loss in the PFC (Radley et al., 2006), a more in-depth
investigation of spine type shows a decrease in large ‘mushroom’ spines but an increase in
smaller ‘thin’ spines (Radley et al., 2008). Thus, although the net difference in spine number
is the same, these morphological shifts may have profound effects on cell physiology
(Figure 3).

Although the focus on plasticity mechanisms has principally been on the postsynaptic
aspect, the presynaptic axon terminal also undergoes reorganization in response to
experience. In 1982, Kandel and Schwartz showed that serotonin-induced upregulation of
cyclic adenosine mono-phosphate (cAMP) is responsible for the increased release of the
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neurotransmitter that results in sensitization in Aplysia (Kandel and Schwartz, 1982).

Presynaptic vesicular release is a multistep process that involves docking of synaptic
vesicles to the active zone of the presynaptic terminal or ‘bouton’, priming of the synaptic
vesicles, and triggering of Ca2+ influx, that leads to the culmination of vesicular fusion and
neurotransmitter release (for a complete review of this process see, Sudhof, 1995, 2004).
The release probability for synaptic vesicles varies from synapse to synapse and depends on
parameters such as the amount of Ca2+ influx per action potential, along with the sensitivity
of vesicles to Ca2+. In primary hippocampal cultures, there are 5–10 docked vesicles ready
to undergo immediate fusion, termed the ready releasable pool (Schikorski and Stevens,
1997). These terminals have been shown to be ‘unreliable’ because synaptic vesicle release
occurs once for approximately 5–10 Ca2+ triggering signals (Dobrunz and Stevens, 1997).
Long-term potentiation (LTP), a persistent increase in synaptic strength due to high-
frequency stimulation of afferent fibers, at the mossy fiber-Ca3 synapse occurs via increased
Ca2+ presynaptically, which increases the reliability of these terminals (Nicoll and Malenka,

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1995). Induction of this form of LTP is impaired by acute stress (Chen et al., 2010).
Interestingly, molecules known to be critical in vesicle docking and priming, such as Rab3-
interacting molecules (RIMs), are required for this form of LTP (Castillo et al., 1997; Lonart
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et al., 2003). Although little is known regarding the role of these presynaptic proteins in
psychiatric disorders, RIM α-knockout mice display schizophrenia-like symptoms, such as
impaired social interaction and prepulse inhibition (Blundell et al., 2010). Further studies are
needed to assess the relative contribution of the presynaptic machinery in stress-induced
plasticity.

Molecular mechanisms of spine adaptations

Attempts to understand stress-induced alterations in dendritic spine morphology and their
underlying mechanisms are disadvantaged by the diversity of morphological modifications
seen across brain regions. This is prominently exemplified by the opposite changes in the
dendritic structure observed in cortical and limbic structures following stressful stimuli. In
the following section, we narrow our focus towards recent findings that have begun to
elucidate the mechanisms of stress-induced dendritic spine remodeling in the NAc and
hippocampus.

Although monoamine depletion has prevailed as the foremost hypothesis on the etiology of
depression (Tissot, 1975; Heninger et al., 1996), in recent years, other systems, such as the
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inflammatory cytokines (Smith, 1991; Ur et al., 1992; de Beaurepaire, 2002), neurotrophic

factors (Nibuya et al., 1995; Chen et al., 2001; Vidal et al., 2011), and the ubiquitous
neurotransmitter glutamate (Palucha and Pilc, 2005; Li et al., 2010), have been shown to be
crucial factors in the pathogenesis of depression. The actions of these systems are known to
rapidly modulate dendritic spine morphology. A series of recent independently reported
findings show that targets directly downstream of proinflammatory cytokines (Christoffel et
al., 2011) and glutamate N-methyl-D-aspartate (NMDA) receptor (Autry et al., 2011; Li et
al., 2011) directly affect stress-induced behavioral and synaptic plasticity. Interestingly,
NMDA antagonists produce rapid antidepressant effects within 24 h following a single
treatment. Considering the delayed onset of efficacy with traditional monoamine therapies,
monoamines may simply be providing a framework that supports the direct actions of these
other signaling systems (Kugaya and Sanacora, 2005). It is clear that investigating the
mechanisms directly involved in synaptic remodeling offers new and exciting therapeutic
avenues (Fuchs et al., 2006; Sandi and Bisaz, 2007; Andrade and Rao, 2010; Gorman and
Docherty, 2010; Vidal et al., 2011).

Brain-derived neurotrophic factor (BDNF) has long been implicated in stress and
depression-induced behavioral and synaptic plasticity in several brain regions (Tsankova et
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al., 2006; Krishnan et al., 2007; Monteggia et al., 2007; Taliaz et al., 2011). In the NAc,
VTA-derived BDNF is required for the development of experience-dependent social
avoidance behavior, an index of depression-like behavior in the CSDS model (Berton et al.,
2006). Additionally, infusion of BDNF into this region is prodepressant, whereas blocking
its action is antidepressant (Eisch et al., 2003). The hippocampus, by contrast, shows
reductions in BDNF levels following multiple stress paradigms (Smith et al., 1995; Gersner
et al., 2010; Zoladz et al., 2011). Supporting a brain region specific effect of BDNF levels
on depressive behaviors, knockdown of BDNF in specific subregions of the hippocampus
leads to the emergence of depressive behaviors (Taliaz et al., 2010). Moreover, chronic
treatment with several different antidepressants following stress reverses this deficit in the
hippocampus (Nibuya et al., 1995), and direct infusion of BDNF into the hippocampus also
has antidepressant activity (Shirayama et al., 2002). Interestingly, both plasma and serum
levels of BDNF are decreased in patients with MDD (Shimizu et al., 2003; Kima et al.,
2007). Antidepressants normalize stress-induced changes in spine density, experimental

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evidence that strengthens the hypothesis that BDNF critically regulates spine plasticity in
depression (Norrholm and Ouimet, 2001; Marchetti et al., 2010). These data support the
common hypothesis that BDNF is involved in initiating plasticity mechanisms and not
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regulating mood states directly.

Recently, we found that a downstream target of BDNF and cytokines, inhibitor of kappa
kinase (IKK), is significantly upregulated in the NAc following CSDS in mice (Christoffel
et al., 2011). IKK is an upstream effector of nuclear factor κB (NFκB), which is a dimeric
transcription factor composed of different combinations of the following subunits: p50,
RelA/p65, c-Rel, RelB, and p52 (Häcker and Karin, 2006). In its inactive conformation,
NFκB is sequestered in the cytoplasm by inhibitor of kappa B (IκB). After phosphorylation
by IKK and subsequent polyubiquitylation, IκB is degraded by proteosomes. Now released
and active, the NFκB subunits are free to translocate from the cytoplasm into the nucleus
and initiate transcription of target genes (Gutierrez et al., 2005). Early studies found that
NFκB is activated in a Ca(2+)/calmodulin-dependent kinase (CaMKII) dependent manner,
that the p65:p50 heteromer is selectively localized to synapses, and that activated p65 is
translocated into the nucleus following experience-dependant activation (Meffert et al.,
2003). Furthermore, p65-deficient mice lacking synaptic NFκB expression were unable to
learn spatial memory tasks, directly implicating NFκB-modulated gene transcription in
behavioral and synaptic plasticity. Furthermore, evidence exists suggesting that NFκB
signaling in neurons is far more complicated than initial reports indicate. Depending on the
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mechanism of NFκB p65 phosphorylation, NFκB is able to exert potent inhibitory or

promotional effects on neurite growth in the same neurons (Gutierrez et al., 2008). In the
NAc, viral-mediated gene transfer of a constitutively active IKK mutant results in increases
in the number of dendritic spines on NAc neurons, whereas inhibition of NFκB by
expression of a dominant negative IKK mutant decreases basal dendritic spine number
(Russo et al., 2009). We also found that inhibition of IKK signaling following CSDS
reverses the increase in spines as well as social avoidance behavior, which suggests that
NFκB-dependent changes in neuronal morphology in the NAc are driving aspects of stress-
induced behavioral plasticity.

These data all lead towards a singular question: what is the intracellular mechanism directly
responsible for modifying the actin cytoskeleton following stressful stimuli? Dendritic
spines are composed primarily of actin filaments modulated by cytoskeletal remodelers and
capped by a postsynaptic density containing complexes of receptors along with signaling
and scaffolding proteins (Arellano et al., 2007; Bourne and Harris, 2008). Although data
examining stress-induced alterations at this level are sparse, there is considerable literature
examining this question in other neuropsychiatric disorders (Bozdagi et al., 2010; Hayashi-
Takagi et al., 2010; Peca et al., 2011) that clearly implicates actin reorganization as a critical
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step for synaptic and behavioral plasticity.

Reorganization of the actin cytoskeleton is modulated, to a large extent, by members of the

small G protein RhoGTPase family, including Rac1, Cdc42, and RhoA, through activation
by guanine nucleotide exchange factors (GEFs) or inactivation by GTPase-activating
proteins (GAPs) (for a complete review, see Tolias et al., 2011). This family of proteins has
been heavily implicated in spinogenesis in several neuronal systems (Nakayama and Luo,
2000; Luo, 2002; Meng et al., 2003; Negishi and Katoh, 2005; Newey et al., 2005; Penzes et
al., 2008). Although 58 Rho-GEFs, 56 Rho-GAPs, and 20 Rho-GTPases have been
identified in the mouse genome (Kiraly et al., 2010a), we currently have very little
understanding of their roles in the NAc, basally, or in response to stressful stimuli. However,
it is worth noting that administration of cocaine regulates the GEF Kalirin-7 in the NAc and
results in alteration in dendritic spine morphology (Kiraly et al., 2010b). Based on the
similarities observed in the NAc following either stress or administration of drugs of abuse

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(Miczek et al., 2008), it is interesting to speculate on the role of RhoGTPases in stress-

induced dendritic spine morphology.
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Live imaging of spines

Studies of spine density changes have become routine in animal models of disease, but the
ultimate impact of these changes on neuronal activity is poorly understood. Changes in spine
morphology have been shown to correlate with LTP and long-term depression (LTD) (Van
Harreveld and Fifkova, 1975; Zhou et al., 2004). LTP is known to increase insertion of 2-
amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors into the
synapse (Liao et al., 1995), and spine size and AMPA receptors levels are positively
correlated. Interestingly, a near doubling of stubby spines occurs 10 min after LTP induction
(Chang and Greenough, 1984; Arellano et al., 2007), yet ultrastructural studies have shown
that the total synaptic area along a dendrite after LTP induction in the hippocampus remains
the same (Bourne and Harris, 2010). More specifically, the authors found that the
enlargement of synapses was accompanied by a loss of small synapses, verified in both
excitatory and inhibitory synapses, suggesting that shifts in synapse size and number are
accompanied by homeostatic regulation.

Early research on spines was limited to static snap shots, whereas recent live imaging
techniques provide us with tools necessary to gain a more complete understanding of the
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temporal dynamics of dendritic spine structure and function. For example, using two-photon
microscopy in combination with glutamate uncaging, Kasai and colleagues confirmed that
single spine stimulation, via high frequency release of 4-methoxy-7-nitroindolinyl-caged-L-
glutamate (MNI-glutamate), results in an increase in spine size and synaptic AMPA receptor
currents, which was dependent on CaMKII in hippocampal pyramidal neurons (Matsuzaki et
al., 2004). The same approach has been used to study single spine dynamics in other regions
(Carter and Sabatini, 2004) and is currently the only method available to visually assess
single spine plasticity mechanisms of subcortical regions.

In vivo two-photon studies have demonstrated that a subpopulation of spines are dynamic,
emerging and retracting over the course of days, yet the majority of dendritic spines are
stable across months and possibly even years (Grutzendler et al., 2002). Experience-
dependent learning tends to induce a shift towards larger, more stable spines without
changing the overall spine number, a finding that suggests that the balance between stable
and immature structures is an important aspect of experience-dependent plasticity (Keck et
al., 2008; Yang et al., 2009). Interestingly, Xu et al. demonstrated that spine formation
correlates with the degree of learning in mice on the forelimb motor task and that the
percentage of new spines that persisted predicted long-term performance (Xu et al., 2009).
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These findings beg the question: how do changes in spine density, type, or turnover translate
into functional changes in neuronal activity? Although there is strong evidence that spines
function as biochemical compartments (Denk et al., 1996; Svoboda et al., 1996), their direct
role in controlling the cellular physiology of disease states is still not well understood (Tsay
and Yuste, 2004; Spruston, 2008).

Stress and functional plasticity

Initial attempts to understand the functional implications of spine changes on stress-induced
plasticity have used electro-physiological techniques to assess synaptic plasticity. Patch
clamp recording of single neurons or field recordings from groups or areas in an ex vivo
brain slice preparation have been the primary methods to assess the effects of stress on
functional properties of neurons. For example, MSNs in the NAc shell show an increase in
the AMPAR/NMDAR ratio following forced swim stress, suggesting an overall
strengthening of synapses (Campioni et al., 2009). Similarly, CSDS causes a shift in the

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AMPAR profile with susceptible animals showing a decrease in GluA2 and an increase in
GluA1, which is associated with increased excitability of these neurons (Vialou et al., 2010).
As previously mentioned, CSDS also increases NAc MSN stubby spine formation and the
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frequency of mEPSCs, a functional correlate of increased synapse number (Christoffel et al.,

2011). Interestingly, a mild stressor (performing the Morris water maze in 22°C water)
enhances spatial learning and increases GluA2 at hippocampal synapses in rats. However,
another study showed that in CD-1 mice undergoing an adolescent chronic social stress in an
unstable hierarchy structure, there was a decrease in GLuA1 mRNA expression and an
increase in GLuA2 mRNA expression in CA1 and the dentate gyrus, respectively (Schmidt
et al., 2010). This effect highlights the importance of taking developmental, strain, and
species differences into account when interpreting stress results.

Although less is known regarding other brain circuits, in the amygdala, inescapable
footshock leads to a transient increase in the firing rate of spiny neurons (Pelletier et al.,
2005). Similarly, VTA dopaminergic neurons display an increase in firing rate following
CSDS; however, it is unknown whether structural alterations accompany either of these
changes (Krishnan et al., 2007).

In many brain circuits, there seems to be fairly good overlap between structural and
functional changes. For example, stress increases spine density and results in a
hyperexcitability of amygdala and NAc neurons, whereas stress reduces spine density and
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impairs LTP in the PFC and hippocampus pyramidal neurons (Rosenkranz et al., 2010). Foy
et al. showed that tail-shock and restraint stress impairs LTP and enhances LTD in the CA1
region of the hippocampus (Foy et al., 1987; Xu et al., 1997). Not surprisingly, plasticity
impairments due to stress can result in dysfunction of signaling between brain regions. For
example, CUS impairs LTP at PFC synapses receiving hippocampal innervations (Cerqueira
et al., 2007), as well as at those receiving thalamic innervations (Quan et al., 2011).
Collectively, these studies suggest that spines serve as biochemical compartments whose
signaling pathways lead to alterations in the strength of a particular connection, which is
dependent upon the presynaptic innervations they receive. Future studies to dissect circuit
level changes in the structure and function of synapses undergoing plasticity will give us
greater insight into how the brain functions during periods of stress to guide behavior.

Human studies
In clinical populations, experience of depression and stress is often correlated with changes
in the total volume and activity of a region. Pizzagalli and colleagues demonstrated that
anhedonia, a core symptom of depression, is correlated with a reduction in NAc volume and
NAc responsiveness to rewarding stimuli (Pizzagalli et al., 2009; Wacker et al., 2009).
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Similarly, reduced volumes in other mesolimbic regions, such as the PFC, are observed in
depressed patients (Drevets et al., 1998; Videbech and Ravnkilde, 2004; Koolschijn et al.,
2009). Because longitudinal studies tracking individuals before the onset of depression are
lacking, it is unclear whether these changes are due to stressful life events or preexisting
vulnerabilities to developing depressive disorders. Further complicating the issue, clinical
and basic science findings are only partly consistent. For example, in the hippocampus there
is a stress-induced shrinkage of hippocampal neurons in rodents and reduced volume in
depressed human patients. Additionally, elevated glucocorticoid levels, seen in depressive
populations, can lead to hippocampal atrophy in rodents, a finding that suggests that HPA
axis activation is partly responsible for reduced hippocampus volumes in humans (Woolley
et al., 1990). However, the finding that NAc MSNs show increased spine density is not
easily reconciled with a human decrease in NAc volume and responsiveness to rewarding
stimuli. In fact, drug abuse models would suggest that increased branching of dendrites and
spine density is correlated with behavioral sensitization to the rewarding effects of a drug

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 Christoffel et al. Page 10

(Russo et al., 2010). Moreover, there seems to be even greater inconsistency in the
amygdala, where studies have shown an increase, decrease, or no change in volume
(Bremner et al., 2000; Caetano et al., 2004; Lorenzetti et al., 2010). A meta-analysis of
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studies looking at amygdala volumes found no changes in depressed patients (Koolschijn et

al., 2009); however, another study found an increase in cerebral blood flow to the amygdala,
a correlate of neuronal activity (Drevets et al., 2008). Rodent models somewhat confirm
these latter results and show that stress induces dendritic hypertrophy, increased spine
density, and hyperexcitability within the amygdala. These apparently conflicting clinical and
basic findings could be due to heterogeneous clinical populations, where depression is
comorbid with other psychiatric illness, or medication effects, as some patients were
undergoing treatment during the experiments. At the same time, the stress paradigms used in
basic research are incomplete models not capable of fully recapitulating the human disease
state. Furthermore, most of the basic science findings were gathered from adult rodent stress
and do not take into account early life stress, which has been shown to play a pivotal role in
the development of mood disorders.

As new technologies in basic and clinical research become available, we will be able to
better determine the relevant functional and structural changes important in depression and
other stress disorders. Recent progress in the development of new analytic techniques for
functional magnetic resonance imaging (fMRI) data, such as independent component
analysis or region-of-interest (ROI) analysis, is already providing a more comprehensive
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look at the interaction among brain regions in mood disorders (Fox et al., 2007). One study,
using ROI analysis, uncovered a decreased connectivity of frontal-limbic circuits in
depressed patients (Lui et al., 2011). Likewise, on the preclinical side, optogenetics now
allows us to study the functional relevance of neuronal activity on circuit level fMRI
responses and depression-like behavior. In a seminal study, Deisseroth and colleagues
showed that stimulation of the thalamus with channel-rhodopsin (ChR) increased activity in
the somatosensory cortex measured by fMRI (Lee et al., 2010). Furthermore, blue light
stimulation of ChR in frontal cortex pyramidal neurons reduces the prodepressant effects of
CSDS while stimulation of NAc alters reward-related behavior (Covington et al., 2010;
Lobo et al., 2010). This approach is mirrored in clinical studies where deep brain stimulation
(DBS) in the cortex and NAc is effective in alleviating symptoms in treatment-resistant
depressed patients (Lozano et al., 2008; Bewernick et al., 2010). Optogenetics provides an
excellent tool to parse circuits and cell types responsible for the therapeutics effect of DBS,
and will assist in the refinement of this treatment modality. More broadly, we now have
tools to uncover how system level signaling controls behavior. As more sophisticated tools
are developed, our ability to take hypotheses from the basic sciences to the clinic will
increase exponentially.
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Conclusions
Correlative evidence about the function of spines has greatly informed neuroscience and
aided in understanding the pathology of brain diseases. However, novel investigative tools
are now uncovering causative evidence for synaptic plasticity in controlling depression-
related behavior. Our ability to not only observe and characterize but also manipulate the
biological function of spines is a revolutionary advance in the study of synaptic plasticity.
Longitudinal studies of spine and neuronal dynamics, in combination with stress and genetic
models of disease, will pave the way for clarification of the etiology of synaptic
dysregulation in psychiatric disease. Yet, there are still many important questions that must
be resolved (Box 1). Although we have moved beyond the monoamine hypothesis and
recognize that psychiatric disease reflects a disruption in normal plasticity mechanisms, the
influence of these complex adaptations on behavior is only beginning to be discovered.
Furthermore, it is crucial to continue to improve clinical diagnostic and analytical tools.

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 Christoffel et al. Page 11

Doing so will aid both in the diagnosis of psychiatric disease and our ability to translate
basic findings into effective therapies.
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Box 1 Outstanding questions

1. Are synaptic alterations the cause of maladaptive behavior or a correlative
response of stressful experience?
2. Do different intracellular signaling pathways or different synaptic inputs
account for the reversibility of spine changes on particular neuron types?
3. Do specific neurotransmitters cause distinct synaptic adaptations?
4. What is the functional relevance of shifts in dendritic spine size and/or number?
5. What mechanisms determine the directionality of changes in spine size and/or
number?

Acknowledgments
This work was supported by a US National Institute of Mental Health grant 1R01MH090264-01A1 (S.J.R.).
NIH-PA Author Manuscript

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Biographies
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Daniel J. Christoffel BA, is a graduate student in the laboratory of Dr. Russo in the
Neuroscience Department at the Mount Sinai School of Medicine. He obtained his BA in
Psychology and Philosophy at New York University. His thesis studies focus on the role of
inhibitor of kappaB kinase in stress-induced synaptic plasticity and depressive behaviors.

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 Christoffel et al. Page 20
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Scott J. Russo, PhD, is an Assistant Professor of Neuroscience at the Mount Sinai School of
Medicine. He did his PhD in Biopsychology at The Graduate Center of CUNY and a
postdoctoral fellowship in Psychiatry at The University of Texas Southwestern Medical
Center. His work focuses on the molecular mechanisms that control synaptic plasticity of
reward circuitry in stress- and addictive-disorders.

Sam A. Golden is a graduate student in the Russo laboratory at the Mount Sinai School of
Medicine. Prior to his matriculation at the Mount Sinai School of Medicine, he was an
Intramural Training Award Fellow at the National Institute of Drug Abuse. His work has
focused on identifying the intracellular mechanisms underlying drug and stress-induced
synaptic plasticity in the mesolimbic dopaminergic reward circuit, and evaluating their
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potential for therapeutic innovation.

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 Christoffel et al. Page 21
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Figure 1. A sagittal brain slice showing the mesocorticolimbic reward circuitry of the brain,
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highlighting the major neuron type of each region

Projections of VTA dopamine neurons (shown in solid red lines) impinge directly on NAc
and mPFC neurons, as well as on amygdala and hippocampal neurons (the latter projections
are not shown in the figure). The solid purple line represents GABAergic afferents (some
direct, some indirect) from the NAc to the VTA, which provide feedback to VTA dopamine
neurons. The dotted purple lines represent glutamatergic afferents to the NAc from mPFC,
amygdala, and hippocampus. Each structure contains specialized neuronal cell types thought
to play an integral role in the complex behavioral phenotypes associated with reward-related
behavior. These cell types, color-coded in the key, include amygdala (green) and NAc
(purple) spiny neurons, PFC (pink) and hippocampal CA3 (blue) pyramidal neurons, and
VTA dopamine neurons (red). Below, cartoon renderings of the affect of stress on neuronal
morphology, along with a description of the normal function and pathophysiology of
plasticity within each mesocorticolimbic brain region.

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 Christoffel et al. Page 22
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Figure 2. Region specific effects of stress on spine plasticity

(A) In the NAc, one study has found a doubling of stubby spines after CSDS. To date, no
other studies have examined spine reorganization following stress. (B) In the amygdala,
several studies have found a stress-induced increase in dendritic length and spine density;
however, there are no studies that have examined changes in spine morphologies. (C) In the
PFC, the majority of studies found that stress causes a reduction in dendritic length and
spine density. It seems that these changes in density are specific to spine types. Note the
increase in thin spines but decrease in mushroom spines. (D) Although there are conflicting
reports*, several studies would support the hypothesis that the dendritic atrophy of
hippocampal pyramidal neurons is accompanied by spine loss.

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 Christoffel et al. Page 23
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Figure 3. Model of interactions between spine type and dopamine and glutamate
neurotransmitter systems in the NAc
Spine morphology is an important determinant of synaptic strength. Larger mushroom
spines have more AMPA receptors than smaller thin and stubby spines. However,
morphology may also have an important impact on responsiveness to different
neurotransmitters. Stubby spines, which lack a traditional spine neck, may either receive less
or contain very different connections with dopamine terminals extending from the VTA and
substantia nigra than thin or mushroom spines. Future studies aimed at characterizing the
function of specific terminal populations will further elucidate neurotransmitter specific
effects on postsynaptic signaling. (From left to right, stubby spine, thin spine, and
mushroom spine.)
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 Christoffel et al. Page 24

Table 1
Regions specific affects of multiple stressors on synaptic plasticity.
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Region Stress Structure/function adaptation (references) Clinical findings (reference)

PL Restraint ↓Dendritic length (Cook and Wellman, 2004; Radley et al., ↓Volume (Drevets et al., 1998; Videbech
2006) and Ravnkilde, 2004; Koolschijn et al.,
2009)
↓Spine density (Radley et al., 2006, 2008) ↓CBF and metabolism (Drevets et al.,
2008)
↓Thin spines (Radley et al., 2008)
IL Restraint ↓Dendritic length (Goldwater et al., 2009; Shansky et al., N/A
2009)
↓Spine density (Goldwater et al., 2009)

BLA-projectinga (Shansky and Morrison, 2008)

oPFC Restraint ↑Dendritic length (Liston et al., 2009) ↓Volume (Drevets et al., 2008)
Amy Restraint† ↑Dendritic length† (Vyas et al., 2003; Mitra et al., 2005) ↑Volume (Bremner et al., 2000)

Inhibitory avoidance* ↑Spine density† (Vyas et al., 2006) ↓Volume (Caetano et al., 2004)

↓Spine density† (Bennur et al., 2007) ↑CBF (Drevets et al., 2008)

↑Firing rate* (Pelletier et al., 2005)

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Hip Restraint ↓Dendritic length (Magarinos and McEwen, 1995; Sousa et ↓Volume (Bremner et al., 2000; Videbech
al., 2000) and Ravnkilde, 2004)
↑Synaptic vesicle density (Magarinos et al., 1997) ↓CBF and metabolism (Drevets et al.,
2008)
NAc CSDS‡ ↑Stubby spines† (Christoffel et al., 2011) ↓Volume (Pizzagalli et al., 2009; Wacker
et al., 2009)
Forced ↑mEPSCs† (Christoffel et al., 2011) ↓Reduced responsiveness to rewards
swim** (Pizzagalli et al., 2009; Wacker et al.,
↑Inward rectification† (Vialou et al., 2010) 2009)

↑AMPA/NMDA ratio* (Campioni et al., 2009)

VTA CSDS ↑Firing rate of DA neurons (Krishnan et al., 2007) N/A

†
Restraint stress.
*
Inhibtory avoidance.
‡
CSDS.
**
Forced swim.
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Amy, amygdala; BLA, basolateral amygdala; Hip, hippocampus; IL, infra-limbic cortex; NAc, nucleus accumbens; oPFC, orbital frontal cortex;
PL, prelimbic cortex; VTA, ventral tegmental area; AMPA, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; CBF, cerebral blood flow; DA,
dopamine; mEPSCs, miniature excitatory postsynaptic currents; NMDA, N-methyl-D-aspartate; N/A, not available.
a
No change.

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