Stress and excitatory synapses: From health to disease

Neuroscience 248 (2013) 626–636

NEUROSCIENCE FOREFRONT REVIEW STRESS AND EXCITATORY SYNAPSES: FROM HEALTH TO DISEASE W. TIMMERMANS, a1 H. XIONG, a1 C. C. HOOGENRAAD b AND H. J. KRUGERS a*

Exposure to chronic stress Early life experience and excitatory synapses Stress and excitatory synapses in health and disease Summary and future perspectives References

a

Swammerdam Institute for Life Sciences, SILS-CNS, Science Park 904, 1098 XH Amsterdam, The Netherlands b Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands

Abstract—Individuals are exposed to stressful events in their daily life. The effects of stress on brain function ranges from highly adaptive to increasing the risk to develop psychopathology. For example, stressful experiences are remembered well which can be seen as a highly appropriate behavioral adaptation. On the other hand, stress is an important risk factor, in susceptible individuals, for depression and anxiety. An important question that remains to be addressed is how stress regulates brain function and what determines the threshold between adaptive and maladaptive responses. Excitatory synapses play a crucial role in synaptic transmission, synaptic plasticity and behavioral adaptation. In this review we discuss how brief and prolonged exposure to stress, in adulthood and early life, regulate the function of these synapses, and how these effects may contribute to behavioral adaptation and psychopathology. Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

INTRODUCTION In our daily life we are exposed regularly to emotionally arousing and stressful experiences. These events are remembered better than situations with less emotional value (McGaugh, 2000) an effect which may be highly adaptive from the evolutionary point of view since it promotes coping with comparable situations in the future. The behavioral adaptation to stress is mediated by physiological responses which are initiated upon exposure to stressful experiences (Kim and Diamond, 2002; de Kloet et al., 2005). One of the core neuroendocrine reactions in response to stressful experiences is the activation of the autonomic nervous system (ANS), which results in a rapid release of noradrenaline in the brain (Fig. 1A). Noradrenergic projections arising from the locus coeruleus (LC) regulate neuronal function via b-adrenergic receptors (b-AR) in areas which are critically involved in learning and memory such as the hippocampus, prefrontal cortex, and amygdala, (Gibbs and Summers, 2002; Roozendaal et al., 2009). Stressful events also activate the hypothalamus–pituitary–adrenal (HPA) axis. This results in the release of corticotropinreleasing hormone (CRH) which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland and finally the release of glucocorticoid hormones from the adrenal cortex (corticosterone in most rodents; cortisol in humans). Corticosteroid hormones enter the brain and bind to two subtypes of discretely localized receptors, i.e. the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which (like adrenergic receptors) are expressed in regions that are critical for memory formation such as hippocampus, amygdala, and prefrontal cortex (De Kloet et al., 2005). MRs are occupied when hormone levels are low and exert their effects classically via the genome. GRs have a 10-fold lower affinity for corticosterone, become substantially activated when hormone levels rise after

Key words: stress, AMPA, NMDA, synapses, corticosterone, plasticity. Contents Introduction Stress-hormones and behavioral adaptation Stress and disease Excitatory synapses Stress and synapses Brief exposure to stress

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*Corresponding author. Tel: +31-20-5257621; fax: +31-205257934. E-mail address: [email protected] (H. J. Krugers). 1 These authors contributed equally to this work. Abbreviations: ACTH, adrenocorticotropic hormone; a-AR, aadrenergic receptor; AMPA, a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid; ANS, autonomic nervous system; b-AR, badrenergic receptor; CaMKII, Calcium-Calmodulin-dependent kinase II; CRH, corticotropin-releasing hormone; GR, glucocorticoid receptor; HPA-axis, hypothalamus–pituitary–adrenal axis; LC, Locus Coeruleus; LG, licking grooming; LTD, long-term depression; LTP, long-term potentiation; mEPSCs, miniature excitatory postsynaptic currents; MR, mineralocorticoid receptor; NMDA, N-methyl-D-aspartate; PFC, prefrontal cortex; PKA, Protein kinase A; PKC, Protein Kinase C; PSD, postsynaptic density; PTSD, posttraumatic stress disorder; REST, repressor element 1 silencing transcription factor; SGK, serum and glucocorticoid-inducible kinase.

0306-4522/13 $36.00 Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuroscience.2013.05.043 626

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Stress

LC/NA

HPA axis Hypothalamus/CRH Pituitary/ACTH Adrenal cortex/ glucocorticoids

β-AR

Concentration

ANS

Noradrenaline

Glucocorticoids

MR/GR

Hippocampus Amygdala PFC

Stress

Time (hr)

A

B

Fig. 1. Neuro-endocrine reactions in response to stressful exposure. (A). Exposure to stressful events elicits the rapid release of noradrenaline in the brain (green). After a stressful event, also corticosteroid levels start to rise (blue). Noradrenaline levels rapidly return to baseline, however, corticosteroid levels still rise. Corticosteroids and noradrenaline also in synergy determine synaptic function. Moreover, both hormones can initiate effects that even last when levels are returned back to baseline (purple) (B). ANS: autonomic nervous system; NA: noradrenaline; LC: locus coeruleus; b-AR: b-adrenergic receptors; PFC: prefrontal cortex; HPA-axis: hypothalamus–pituitary–adrenal axis; CRH: corticotropin-releasing hormone; ACTH: adrenocorticotropic hormone; MR: mineralocorticoid receptor; GR: glucocorticoid receptor.

stress and also exert slow genomic actions in cells carrying the receptor (Fig. 1B). Recent evidence has revealed that corticosteroid hormones can also regulate synaptic function via non-genomic effects, both via activation of MRs and GRs (Orchinik et al., 1991; Venero and Borrell, 1999; Di et al., 2003; Karst et al., 2005, 2010; Groc et al., 2008). Corticosteroid hormones, noradrenaline and other neuromodulators (such as CRH and encocannabinoids) in concert regulate learning and memory processes and enable behavioral adaptation to stressful events (Joe¨ls et al., 2006, 2011). In this review we will mainly focus on noradrenaline and corticosteroid hormones, unless mentioned otherwise.

STRESS-HORMONES AND BEHAVIORAL ADAPTATION Noradrenaline and corticosteroid hormones, via their receptors, modulate the enhanced memory formation of experiences with emotional value (Joe¨ls et al., 2006, 2011; Roozendaal et al., 2009). In various learning tasks, noradrenaline facilitates memory formation of emotionally arousing events via brain b-ARs receptors (Hu et al., 2007; Roozendaal et al., 2009; Cahill et al., 1994). Activation of a-adrenergic (a-ARs) receptors also enhances memory, but presumably act by enhancing badrenergic actions (Ferry et al., 1999a,b). Corticosteroid hormones also modulate memory formation. Via activation of MRs corticosteroid hormones modulate appraisal and response selection during the learning process (Oitzl and DeKloet, 1992; Sandi and Rose, 1994). More recent studies show that MRs are also involved in encoding of information, possibly linked to their effects on appraisal and/or response selection (Zhou et al., 2010). Accordingly, genetic deletion of MRs in the forebrain results in cognitive impairments, (Berger et al., 2006; Zhou et al.,

2010, 2011b). Via activation of GRs, corticosteroid hormones promote long-term consolidation of information (Corodimas et al., 1994; Sandi and Rose, 1994; Pugh et al., 1997a,b; De Kloet et al., 1999; Oitzl et al., 2001; Hui et al., 2004; Donley et al., 2005; Joe¨ls et al., 2006; Roozendaal et al., 2009). These memory consolidation-enhancing effects involve GRs acting via homodimerization (Oitzl et al., 2001), but other GRdependent pathways may also be involved. For instance, a recent study suggests that membraneassociated GRs promote long-term memory in an object recognition task via chromatin modification (Roozendaal et al., 2010). Furthermore, corticosteroids act in concert with other hormones such as noradrenaline (Roozendaal et al., 2006, 2009), endocannabinoids (Campolongo et al., 2009) and CRH (Roozendaal et al., 2008) for optimal memory performance both in humans and rodents (De Quervain et al., 2009; Roozendaal et al., 2009). These effects are not unique for rodents, but have also been described in humans (for review see Joe¨ls et al., 2011; Krugers et al., 2012).

STRESS AND DISEASE While the acute response to stressful experiences is highly adaptive, exposure to stressful experiences is also an important risk factor for the development of psychopathology in susceptible individuals. For example, if the stress response is inadequate or excessive and prolonged, the hypersecretion of corticosteroids increases the risk for depression (Stetler and Miller, 2011). Thus, many (but not all) patients with depression have disturbed HPA-axis regulation, and longitudinal studies show not only that patients do not respond well to antidepressants if HPA-axis disturbance persists, but also that clinically remitted patients whose HPA disturbance reappears are at high risk of relapse (De Kloet et al., 2005). Moreover, studies in healthy individuals who

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belong to families with a high genetic load for depression, indicate that subtle changes of HPA-axis function are a genetic trait that increases the risk of developing depression and antagonists of GRs exert rapid antidepressant actions (Belanoff et al., 2002; DeBattista et al., 2006; Blasey et al., 2011; Watson et al., 2012). Collectively, these observations support the view that HPA-axis dysregulation, possibly as a genetic predisposition, is a risk factor for depression. In addition, stressful experiences can also trigger posttraumatic stress disorder (PTSD) in susceptible individuals and enhanced sympathetic nervous system activity combined with hypocortisolaemia has been found in patients with PTSD (Yehuda, 2001). In addition, enhanced cortisol levels in high-threat conditions hamper the ability to make correct predictions of threat which promote a state of fear which is characteristic for PTSD (Kaouane et al., 2012). These studies indicate that – at least in vulnerable individuals – alterations in stressresponsiveness are related to various forms of psychopathology. An important question is therefore not only how corticosteroid hormones and noradrenaline regulate neuronal function and promote behavioral adaptation but also how their action(s) result in diseaselike conditions such as seen in depression and PTSD. Excitatory synapses play a crucial role in synaptic transmission, synaptic plasticity and learning and memory processes, which are crucial for behavioral adaptation (Kessels and Malinow, 2009). Recent studies have demonstrated that corticosteroid hormones and noradrenaline – alone and together – dynamically regulate these synapses (Krugers et al., 2012). Moreover, these synapses are largely modulated by negative early life experiences which – via epigenetic programing – determine stress-responsiveness and regulate the risk to develop psychopathology (Bagot et al., 2012; Rodenas-Ruano et al., 2012). In this review we will unify these and other recent studies and discuss how regulation of excitatory synapses by stresshormones and early life experiences play a role in behavioral adaptation and might be related to disease. While some studies report effects of stress on metabotropic glutamate receptors (Wagner et al., 2013), we will focus in this review on the regulation of ionotropic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors) and N-methyl-D-aspartate receptors (NMDA receptors). Although recent studies indicate that noradrenaline and corticosteroid hormones regulate hypothalamic synapses (Inoue et al., 2013; Wamsteeker Cusulin et al., 2013), we will describe their actions on these synapses in hippocampus, prefrontal cortex and amygdala, areas which are crucial for cognitive processes.

EXCITATORY SYNAPSES Excitatory neuronal transmission – mediated via glutamate – is particularly important for synaptic transmission, synaptic plasticity and learning and memory processes (Neves et al., 2008). Postsynaptic AMPA receptors mediate most of the fast excitatory

synaptic transmissions in the brain. These receptors are heteromeric tetramer complexes that consist of different combinations of GluA1, GluA2, GluA3 and GluA4 subunits (Nakagawa, 2010). In the mature brain, AMPA receptors are composed mainly of GluA1/GluA2 and GluA2/GluA3 heteromers (Kessels and Malinow, 2009). In dendritic regions, AMPA receptors can be found in various non-synaptic compartments: (i) intracellular in the dendrite, (ii) intracellular in the spine, (iii) on the dendritic surface (which is generally lacking excitatory synapses), or (iv) on the spine surface but outside the synapse (Kessels and Malinow, 2009; Anggono and Huganir, 2012; Park et al., 2004; Park et al., 2006; Ehlers et al., 2005; Newpher and Ehlers 2008). Inside dendrites, trafficking of AMPA receptors to and from the synapse is regulated by two main processes: exocytosis and endocytosis between intracellular and membrane receptor pools, and surface diffusion between extrasynaptic and synaptic receptor pools (Petrini et al., 2009) (Fig. 2A). The insertion of AMPA receptors into the plasma membrane through exocytosis is a key step in controlling the number of receptors at the cellular membrane Shi et al., 2001. Although the exact localization and nature of AMPA receptor insertion is still debated, live-imaging experiments have shown that exocytotic events occur in the dendritic shaft and may also happen in dendritic spines (Petrini et al., 2009; Kennedy et al., 2010; Henley et al., 2011). AMPA receptors are internalized, through endocytosis, close to the postsynaptic density (PSD) and in the extra-synaptic membrane. A two-step model has thus emerged in which AMPA receptors first traffic from and to the plasma membrane, lateral to synapses, and then, at the neuronal surface, diffuse from extra-synaptic sites to synaptic membrane compartments. In line with this model, recent studies have shown that the delivery of AMPA receptors from intracellular stores to the synapse depends on extra-synaptic receptor exocytosis (Lu et al., 2007; Petrini et al., 2009). AMPA receptors also play a crucial role in synaptic plasticity paradigms such as seen in long-term potentiation (LTP) and long-term depression (LTD) (Kessels and Malinow, 2009; Granger et al., 2012). LTP is accompanied by enhanced exocytosis of AMPA receptors , which mostly originate from endosomal compartments as well as lateral diffusion of AMPA receptors (Makino and Malinow, 2009). The exocytosed receptors, at extra-synaptic sites or near the spines, then diffuse and accumulate at postsynaptic density compartments (Makino and Malinow, 2009; Petrini et al., 2009; Kennedy et al., 2010; Van der Sluijs and Hoogenraad, 2011). These studies indicate that the regulation of synaptic AMPA receptors relies on a dynamic equilibrium between intracellular, extra-synaptic and synaptic pools which is regulated not only by the activity status of the neuronal network but also by posttranslational modifications of AMPA receptors (Lu and Roche, 2012). In addition, synaptic insertion of AMPA receptors is also necessary to increase and stabilize the size of dendritic spines (Passafaro et al., 2003; Kopec et al., 2007; Saglietti et al., 2007).

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Fig. 2. Effects of different forms of stress on synapses. Baseline levels of AMPARs and NMDARs. The expression of receptors is highly dynamic. A two-step model has emerged. Receptors are first exocytosed lateral to the synapse followed by lateral diffusion upon which they reach the synapse. Endocytosis of receptors occurs closely to the PSD. The amount of receptors present at the surface membrane relies thus on a dynamic equilibrium between intracellular, extra-synaptic and synaptic pools. Under baseline conditions, the MR is already occupied (A). During a brief exposure to stress, glucocorticoids, via the MR, stimulate the presynaptic release of glutamate and postsynaptic lateral diffusion of both AMPARs and NMDARs via a non-genomic way (B). After a brief exposure to stress, corticosteroid levels start to rise and now also mediate slow genomic effects via both MRs and GRs. Via GRs, exocytosis and lateral diffusion of both AMPARs and NMDARs are enhanced and more receptors are inserted into the synaptic membrane (C). After chronic stress, the amount of surface receptor expression is greatly reduced. These effects are mediated by enhanced ubiquitin/proteasome-mediated degradation (D). The function of synapses is also altered by early life experiences and maternal care. Surface expression of NMDARs is increased accompanied by an enhanced receptor functioning which cannot be further enhanced by stress. PSD: postsynaptic density; MR: mineralocorticoid receptor; GR: glucocorticoid receptor.

Changes in synaptic plasticity and AMPA receptor dynamics can be elicited by activation of NMDA receptors. The NMDA receptor forms a heterotetramer of two GluN1 and two GluN2 subunits; two obligatory GluN1 subunits and two localized GluN2 (GluN2A and/ or GluN2B) subunits. Activation of NMDA receptors – which requires presynaptic glutamate release and postsynaptic depolarization triggers calcium influx into postsynaptic cells. Calcium permeability of NMDA receptors is largely modulated by the expression of GluN2A and GluN2B subunits. Whereas GluN2B is predominant in the early postnatal brain, the number of GluN2A subunits grows, and eventually GluN2A subunits outnumber GluN2B (Rodenas-Ruano et al., 2012). This is relevant for synaptic plasticity since GluN2B-containing NMDA receptors generally facilitate synaptic plasticity (Massey et al., 2004). Calcium

entering postsynaptic cells via NMDA receptors activates several kinases i.e. which are crucial for establishing synaptic plasticity (Malenka and Nicoll, 1999; Neves et al., 2008). In particular, CalciumCalmodulin-dependent kinase II (CaMKII), Protein kinase A (PKA) and Protein Kinase C (PKC) have been reported to determine synaptic potentiation (Esteban et al., 2003). Phosphorylation of GluA1 at serine 818 (S818) by PKC is a critical event in the plasticity-driven synaptic incorporation of AMPA receptors (Boehm et al., 2006), while phosphorylation of S831 by CaMKII and PKC and phosphorylation of S845 by PKA affects the open-channel probability of the receptor but may also regulate the synaptic incorporation of AMPA receptors on the surface (Esteban et al., 2003). Recently, it was found that PKC phosphorylation at S816 and S818 residues of GluA1 enhanced the binding of an actin-

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binding protein 4.1N to GluA1, thereby facilitating extrasynaptic GluA1 insertion which is critical for LTP induction (Lin et al., 2009). Moreover, genetically modified mice with knock-in mutations that block GluA1 phosphorylation, showed that S831 and S845 are critical for synaptic plasticity (Lee et al., 2003). Importantly, activation of NMDA receptors and synaptic delivery of AMPA receptors are critically involved in the memory formation of emotionally arousing events Lu et al., 2001; Malinow and Malenka, 2002; Malenka and Bear, 2004. Thus, hippocampal NMDA receptors and NMDA receptor-dependent synaptic plasticity are widely considered to be an important substrate of long-term spatial memory processes (Tsien et al., 1996) although their precise role in memory formation remains to be verified more in detail (Bannerman et al., 2012). Also AMPA receptors are crucial for memory formation. In contextual learning paradigms, the number of GluA1 and GluA2 subunits increases within synapses in hippocampal neurons, indicating that such a cognitive task is accompanied by changes in AMPA receptor trafficking (Whitlock et al., 2006). In addition, newly synthesized AMPA receptors are selectively recruited to mushroom-type spines in adult hippocampal CA1 neurons, 24 h after fear conditioning (Matsuo et al., 2008). Studies using mutant mice reveal that GluA1 deficient mice are hampered in short-term memory processes (Reisel et al., 2002). Moreover, GluA2 deficient mice are impaired in a spatial working memory task and elevated Y-maze (Shimshek et al., 2006). These studies indicate that GluA1 and GluA2 subunits are relevant for memory processes. Finally, the observation that preventing synaptic insertion of GluA1-containing AMPA receptors in the amygdala hampers tone-cue as well as contextual fear conditioning implies that trafficking of GluA1-containing AMPA receptors is critical for the memory formation of emotionally arousing events (Rumpel et al., 2005; Mitsushima et al., 2011).

STRESS AND SYNAPSES Brief exposure to stress Exposure to stress rapidly elicits the release of noradrenaline in the brain (Joe¨ls and Baram, 2009). This rapid release, via activation of b-ARs, activates PKA and CaMKII and increases phosphorylation of GluR1 at S845 and S831 respectively which are critical sites for synaptic delivery of AMPA receptors (Thomas et al., 1996; Hu et al., 2007; Tenorio et al., 2010; Zhou et al., 2011a), both in hippocampus and prefrontal cortex (Joiner et al., 2010). In addition, noradrenaline lowers the threshold for long-term potentiation via a process that requires the phosphorylation of GluR1 (Hu et al., 2007). After exposure to stressful experiences, also corticosteroid levels start to rise (Joe¨ls and Baram, 2009). In the hippocampus, these hormones rapidly and reversibly enhance the frequency of miniature excitatory postsynaptic currents (mEPSCs) via non-genomic effects of membrane-bound MRs, and involve enhanced presynaptic release probability of glutamate (Karst et al.,

2005a). In addition to presynaptic changes, corticosterone – via MRs – rapidly increases postsynaptic lateral diffusion of AMPA receptors, which is critical for synaptic insertion of these receptors (Groc et al., 2008; Opazo and Choquet, 2011). At the same time scale, corticosteroid hormones also rapidly promote the activity-dependent synaptic insertion of AMPA receptors and synaptic potentiation (Wiegert et al., 2006; Groc et al., 2008) (Fig. 2B). After exposure to stress, noradrenaline levels rapidly return to baseline, the GluA1 subunit is no longer phosphorylated by noradrenaline and LTP is no longer facilitated by noradrenaline (Hu et al., 2007). At this moment however, corticosteroid levels can still rise and can also mediate slow genomic effects via MRs and GRs. Via GRs, corticosterone slowly increases surface expression, synaptic insertion, lateral diffusion of both GluA1 and GluA2 subunits and increases the amplitude of mEPSCs (Karst and Joe¨ls, 2005; Groc et al., 2008; Martin et al., 2009) (Fig. 2C). Under these circumstances, corticosterone prevents the activitydependent increase in synaptic AMPARs (Groc et al., 2008) and synaptic potentiation (Alfarez et al., 2002; Krugers et al., 2005) and enables endocytosis of AMPA receptors. This may promote the consolidation of relevant information via metaplastic processes (Krugers et al., 2010). In addition, several recent studies reveal that NMDA receptors are modulated via corticosteroid hormones. Corticosterone, via a rapid non-genomic action enhances NMDA receptor-mediated synaptic response (Tse et al., 2011, 2012), an effect which is largely dependent on the early life experience of the animals (Bagot et al., 2012). Also in the prefrontal cortex (PFC), exposure to stress and corticosterone enhances AMPA and NMDA receptor function. Acute stress, via GRs, increases surface expression of various NMDA receptor subunits and AMPA receptor subunits (GluA1/GluA2) at the postsynaptic membrane. These effects are mediated by an increased activity of Rab4 through serum and glucocorticoid-inducible kinase (SGK) signaling (Yuen et al., 2009, 2011; Liu et al., 2010). Corticosteroid hormones and noradrenaline also in synergy determine synaptic function. Thus, coapplication of these hormones enhances the frequency of mEPSCs, surface labeling and phosphorylation of AMPA receptors (Zhou et al., 2012) and facilitate synaptic potentiation (Pu et al., 2007, 2009). Importantly, this regulation of AMPA receptors by noradrenaline and corticosteroid hormones is critically involved in the memory-enhancing effects of stress (Hu et al., 2007; Yuen et al., 2009; Conboy and Sandi, 2010; Krugers et al., 2010). While most studies on the effects of stress-hormones have been performed on the dorsal hippocampus, recent evidence reveals that the ventral hippocampus – which plays a critical role in emotional memories – is differently regulated by corticosteroid hormones. The ability to elicit long-term potentiation is much lower in the ventral hippocampus when compared to the dorsal hippocampus. Interestingly, acute exposure to a stressful experience as well as direct exposure to

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corticosterone affect the dorsal hippocampus and ventral hippocampus in an opposite manner, causing facilitation of long-term potentiation in the ventral hippocampus and suppression in the dorsal hippocampus (Maggio and Segal, 2007, 2009; Segal et al., 2010). Since these areas differ in efferent connectivity, one interpretation may be that stress regulates the routes by which the hippocampus is functionally linked to the rest of the brain (Segal et al., 2010). Thus, under stress the ventral route to the amygdala may be facilitated which could underlie enhanced formation of emotionally arousing events. Altogether, these hormonal changes of synaptic efficacy can be interpreted as mechanisms to facilitate the storage of relevant information (Krugers et al., 2010; Joe¨ls et al., 2011). Exposure to chronic stress Exposure to prolonged stress has rather negative effects and increases the risk to develop psychopathology – such as depression – in vulnerable individuals. Recent studies also indicate that prolonged exposure to stress affects the function of excitatory synapses. In all hippocampal areas, induction of LTP is greatly impaired after a prolonged period of mild stress or chronic corticosteroid exposure (Bodnoff et al., 1995; Pavlides et al., 2002; Alfarez et al., 2003). Recent studies at the cellular level indicate that prolonged exposure to stress, via corticosteroid actions, inhibits glutamatergic synaptic transmission in the prefrontal cortex. Thus, prolonged stress and elevated corticosteroid hormone levels reduce the surface expression of glutamate receptors (GluN1 and GluA1) (Fig. 2D). These effects are mediated by enhanced ubiquitin/proteasome-mediated degradation and loss of synaptic NMDA receptors and AMPA receptors (Yuen et al., 2012). In addition, decreased levels of GluN2B and GluA2/3 have also been found in the PFC after chronic stress (Gourley et al., 2009). In addition to enhanced corticosteroid hormone levels, also CRH has been implicated in detrimental effects of prolonged stress on hippocampal function (Ivy et al., 2010; Wang et al., 2011a,b). Importantly, disruption of excitatory synaptic transmission after exposure to chronic stress has been implicated in impaired learning and memory (Yuen et al., 2012). Taken together, these data demonstrate that a history of chronic stress exposure disrupts excitatory synaptic transmission and synaptic plasticity. Early life experience and excitatory synapses While many individuals are able to successfully cope with stressful situations, other individuals are at risk to develop stress-related psychopathologies (De Kloet et al., 2005). This underscores the importance of understanding how individual differences in the ability to cope with threatening events later in life, are determined. Individual susceptibility is partly genetically determined. However, environmental influences (particularly early in life) substantially moderate the genetic background. More specifically, it is thought that the quality of parent–

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child interactions during the early postnatal period, in both humans and rodents, modifies brain development and functionality of the HPA-axis such that cognitive and emotional responses later in life are processed in a different way, shifting the risk to develop stress-related psychopathology (Liu et al., 1997; Yehuda, 2001; De Kloet et al., 2005; Hackman et al., 2010; Kessler et al., 2005). Various studies demonstrate that the function of hippocampal excitatory synapses is persistently regulated by early life environment. Rodents exposed to early life stress during the early postnatal period show impaired hippocampal long-term potentiation, reduced hippocampal dendritic complexity as well as impaired spatial learning abilities (Brunson et al., 2005). CRH has been implicated in detrimental effects of early life stress on hippocampal function (Wang et al., 2011a,b). Moreover, hippocampal function and structure is determined by maternal care. Thus, offspring of mothers that were selected of providing high-licking grooming (high LG) and low-licking grooming (low LG) behavior during the first postnatal week display reduced hippocampal (CA1 area and dentate gyrus) synaptic complexity, reduced synaptic plasticity and impaired spatial learning (Liu et al., 2000; Champagne et al., 2008; Oomen et al., 2010; Bagot et al., 2012). Surprisingly little is known how early life experience determines glutamate receptor function. However, a recent study showed that basal NMDA receptor function is enhanced in the offspring of low-LG animals. This is accompanied by elevated GluN1, GluN2A and GluN2Bcontaining NMDA receptors in low-LG animals (Fig. 2E). Interestingly, corticosterone increased NMDA receptor function in high LG animals, but not in low-LG animals (Bagot et al., 2012). This indicates that low-LG offspring exhibits enhanced NMDA receptor function and insensitivity to corticosterone modification. In agreement, maternal deprivation impairs activation of the transcriptional repressor REST (repressor element 1 silencing transcription factor) and the developmental switch from GluN2B to GluN2A-containing NMDA receptors (Rodenas-Ruano et al., 2012). Naturally occurring variations in maternal care in rodents not only influence hippocampal synaptic plasticity; they have been reported to influence hippocampal-dependent cognitive function later in life. The male offspring of mothers that show reduced pup LG exhibit reduced learning and memory in hippocampal-dependent learning tasks (Liu et al., 2000). Moreover, hippocampal neurons in these animals exhibit reduced synaptic plasticity and decreased dendritic complexity (Champagne et al., 2008; Bagot et al., 2009). These cognitive effects are – at least partially – reversed with cross-fostering revealing a direct effect of postnatal maternal care (Liu et al., 2000). Variations in maternal care also determine processing of emotional information later in life. Studies in rodents have demonstrated that adult offspring of mothers that exhibit low (compared to high) levels of maternal care and animals exposed to early life stress display enhanced memory formation for fearful events and

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develop an increased phenotype of anxiety (Weaver et al., 2006; Champagne et al., 2008; Oomen et al., 2010).

STRESS AND EXCITATORY SYNAPSES IN HEALTH AND DISEASE In the previous paragraph we have summarized evidence that stress and stress-hormones modify excitatory synaptic transmission and synaptic plasticity. The regulation of excitatory synapses by brief exposure to corticosterone and/or noradrenaline may underlie the enhanced memory formation of emotionally arousing events (Krugers et al., 2010, 2012). However, stress is also a major risk factor for psychopathology such as seen in PTSD, anxiety and depression. An important question is therefore how stress-induced changes in excitatory synaptic transmission might result in psychopathology. The consolidation and expression of fearful memories are accompanied by enhanced excitatory synaptic transmission and synaptic insertion of AMPA receptors (Rumpel et al., 2005; Zhou et al., 2009; Clem and Huganir, 2010). Corticosteroid hormones and noradrenaline promote the synaptic insertion of AMPA receptors and this is believed to underlie the enhanced memory formation (Hu et al., 2007; Krugers et al., 2012). An important question is why memories remain inappropriately present in some individuals. Corticosteroid hormones and stress in combination with high threat promote PTSD-like memory changes (Kaouane et al., 2012). One possibility is therefore that these hormones, together with noradrenaline enhance synaptic function and consequently memory formation of a fearful event (Krugers et al., 2012). However, it will be equally important to determine whether, and how, these hormones regulate extinction of fearful memories. Moreover, it should be noted that basal cortisol levels are found to be decreased in PTSD patients, while their noradrenergic tone is enhanced (Yehuda, 2001) Since glucocorticoids have been reported to suppress the increase in synaptic plasticity that is mediated by noradrenaline (Pu et al., 2007; Joe¨ls et al., 2011) this could imply that the reduced basal cortisol levels result in a reduced ability to normalize synaptic potentiation after a fearful event, possibly causing exaggerated memory of that particular fearful experience. Alterations in excitatory synaptic transmission have been implicated in stress-related disorders such as depression (Duman and Aghajanian, 2012). For example, Ketamine, which blocks NMDA receptors, has rapid antidepressant actions in patients who are resistant to antidepressants (Berman et al., 2000; Zarate et al., 2006). Accordingly, studies in rodents show that blocking NMDA receptors using Ketamine rapidly reverses chronic stress-induced changes in spine number, synaptic function, anhedonia and anxiety (Liu and Aghajanian, 2008; Li et al., 2010, 2011). Moreover, classical antidepressants such as Imipramine, restore the ability to induce plasticity of excitatory synapses which is suppressed after chronic

stress (Von Frijtag et al., 2002) and also the GR antagonist, Mifepristone – which rapidly restores psychotic depression (Belanoff et al., 2002) – also normalizes synaptic plasticity (Krugers et al., 2006). It remains to be established whether these effects of antidepressant actions are able to restore synaptic levels of NMDA and AMPA receptors which have been reported to be reduced after exposure to chronic stress (Yuen et al., 2012). It is of interest that a recent study has demonstrated that antidepressants directly target AMPA receptors; the antidepressant drug Tianeptine prevents corticosterone-induced changes in AMPA receptor mobility, stabilizes synapses and promotes long-term synaptic plasticity (Kole et al., 2002; Zhang et al., 2012). Also adverse experiences in early life – which enhance disease vulnerability – lastingly regulate excitatory synaptic function. Thus, low levels of maternal care and maternal deprivation persistently enhance hippocampal NMDA receptor function (Bagot et al., 2012; Rodenas-Ruano et al., 2012) via enhancing GluN2B-containing NMDA receptors. This is accompanied by suppressed synaptic plasticity (Champagne et al., 2008; Bagot et al., 2009; Oomen et al., 2010) which can be prevented by blocking NMDA receptors (Bagot et al., 2012). This indicates that early life stress, via disruption of NMDA receptor function, may predispose to cognitive impairment and yield an increased risk to develop psychopathology (Joe¨ls and De Kloet, 2012). Indeed restoring NMDA receptor function in animals which received low levels of maternal care enabled synaptic plasticity (Bagot et al., 2012).

SUMMARY AND FUTURE PERSPECTIVES In this review we have summarized how exposure to stressful experiences and stress-hormones regulate the function of excitatory synapses, and how these effects may underlie behavioral adaptation and disease. Future studies will be necessary to determine whether regulation of excitatory synapses by stress-hormones are confined to the hippocampus or whether they are also present in other brain areas which are critical for cognition, and control of emotional memories such as the PFC and the amygdala. Moreover, the notion that noradrenaline and corticosterone act in concert to modify excitatory synapses, underlines the relevance to examine interactions between various neurotransmitter systems as well (Joe¨ls and Baram, 2009). In addition, not only the interactive effects of stress-hormones need to be examined in detail, but it will be equally important to determine their effects in individuals with a different background of early life experience (e.g. early life stress). Finally, the genetic background – which can serve as a resilience factor or vulnerability factor – needs to be taken into account for a complete appreciation of how stress-hormones in susceptible individuals determine whether the effects of stress will be adaptive or result in enhanced risk to develop psychopathology.

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(Accepted 21 May 2013) (Available online 29 May 2013)