Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal stru...

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Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

Neuroscience xxx (2012) xxx–xxx

REVIEW GLUCOCORTICOID REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR: RELEVANCE TO HIPPOCAMPAL STRUCTURAL AND FUNCTIONAL PLASTICITY D. SURI AND V. A. VAIDYA *

tion of potential therapeutic targets for disorders associated with the dysfunction of stress hormone pathways. This article is part of a Special Issue entitled: Steroid hormones and BDNF. Ó 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Department of Biological Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India

Abstract—Glucocorticoids serve as key stress response hormones that facilitate stress coping. However, sustained glucocorticoid exposure is associated with adverse consequences on the brain, in particular within the hippocampus. Chronic glucocorticoid exposure evokes neuronal cell damage and dendritic atrophy, reduces hippocampal neurogenesis and impairs synaptic plasticity. Glucocorticoids also alter expression and signaling of the neurotrophin, brainderived neurotrophic factor (BDNF). Since BDNF is known to promote neuroplasticity, enhance cell survival, increase hippocampal neurogenesis and cellular excitability, it has been hypothesized that speciﬁc adverse eﬀects of glucocorticoids may be mediated by attenuating BDNF expression and signaling. The purpose of this review is to summarize the current state of literature examining the inﬂuence of glucocorticoids on BDNF, and to address whether speciﬁc eﬀects of glucocorticoids arise through perturbation of BDNF signaling. We integrate evidence of glucocorticoid regulation of BDNF at multiple levels, spanning from the well-documented glucocorticoid-induced changes in BDNF mRNA to studies examining alterations in BDNF receptormediated signaling. Further, we delineate potential lines of future investigation to address hitherto unexplored aspects of the inﬂuence of glucocorticoids on BDNF. Finally, we discuss the current understanding of the contribution of BDNF to the modulation of structural and functional plasticity by glucocorticoids, in particular in the context of the hippocampus. Understanding the mechanistic crosstalk between glucocorticoids and BDNF holds promise for the identiﬁca-

Key words: hormone, glucocorticoid receptor, neurotrophin, tropomyosin-related kinase B, mitogen-activated protein kinase, stress. Contents Introduction 00 Glucocorticoids 00 BDNF 00 Regulation of BDNF 00 Glucocorticoid regulation of BDNF expression 00 Influence of glucocorticoids on Bdnf transcription 00 Influence of glucocorticoids on exon-specific Bdnf transcript variants 00 Influence of glucocorticoids on Bdnf mRNA stability 00 Influence of glucocorticoids on BDNF translation, processing, trafficking and secretion 00 Stress regulation of BDNF 00 Glucocorticoid receptors and BDNF 00 Glucocorticoid regulation of BDNF signaling 00 Glucocorticoids and BDNF crosstalk: implications for hippocampal structural and functional plasticity 00 GC and BDNF interactions in the context of cell survival and structural plasticity 00 GC and BDNF interaction in the context of synaptic plasticity and hippocampal-dependent behavior 00 Conclusions 00 References 00

*Corresponding author. Tel: +91-22-22782608; fax: +91-2222804610. E-mail address: [email protected] (V. A. Vaidya). Abbreviations: ADX, adrenalectomy; AP-1, activator protein-1; BDNF, brain-derived neurotrophic factor; CREB, cyclic AMP response element-binding protein; CRH, corticotrophin-releasing hormone; DG, dentate gyrus; EPSP, excitatory postsynaptic potential; ERK, extracellular signal-regulated kinase; GCs, glucocorticoids; GR, glucocorticoid receptor; GREs, glucocorticoid response elements; HPA, hypothalamo–pituitary–adrenal; JNK, c-Jun N-terminal kinase; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; MKP-1, MAP kinase phosphatase-1; MMPs, matrix metalloproteinases; MR, mineralocorticoid receptor; NF-jB, nuclear factor-jB; p75NTR, p75 neurotrophin receptor; PC, prohormone convertases; PI3-Akt, phosphatidylinositol-3-kinase-Akt; PLCc, phospholipase C-c; PVN, paraventricular nucleus; tPA, tissue plasminogen activator; TrkB, tropomyosin-related kinase B.

INTRODUCTION Steroid hormones serve as a major stress response pathway, evoking widespread responses across the body including the brain, thus priming a ﬁght or ﬂight response (reviewed in Joe¨ls, 2011). Of the steroid hormones, glucocorticoids (GCs) that are secreted by the adrenal cortex in response to physical and psychological stressors, mediate pleiotrophic eﬀects on both the periphery and the central nervous system, evoking diverse changes from the modulation of glucose uptake to inﬂuencing cognitive performance (reviewed in

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Sapolsky et al., 2000). While in the short term these essential hormones play a critical role in promoting stress coping (reviewed in de Kloet, 2008), prolonged elevation of GCs as observed following chronic stress, hypothalamo–pituitary dysregulation, long-term clinical administration, or in Cushing’s syndrome, is associated with several maladaptive changes (reviewed in McEwen, 2008). Chronically elevated GCs have an adverse impact on structural and functional plasticity in limbic brain regions, such as the hippocampus, including spine loss and dendritic atrophy (Liston and Gan, 2011; reviewed in Fuchs et al., 2001), neuronal cell death (Sapolsky et al., 1990; Haynes et al., 2004), impaired long-term potentiation (LTP) (Pavlides et al., 1993, 1996) and decreased neurogenesis (reviewed in Schoenfeld and Gould, 2012). While various studies (Cameron and Gould, 1994; Sousa et al., 2000; Lee et al., 2012) have examined the eﬀects of GCs on plasticity in the brain, a clear mechanistic understanding of the underlying molecular mediators is currently lacking. Growth factors and neurotrophins are key regulators of neuronal plasticity (reviewed in Poo, 2001). In particular, brain-derived neurotrophic factor (BDNF) is reported to strongly inﬂuence synaptogenesis and spine formation (reviewed in Yoshii and Constantine-Paton, 2010), neuronal survival (reviewed in Lipsky and Marini, 2007), LTP and neuronal excitability (reviewed in Minichiello, 2009), as well as adult hippocampal neurogenesis (reviewed in Schmidt and Duman, 2007). Given the opposing eﬀects of GCs and BDNF on many of the same measures of structural plasticity and cellular excitability, it has been hypothesized that speciﬁc adverse eﬀects of GCs may involve attenuation of BDNF expression or signaling (reviewed in Smith, 1996). While such a link has been speculated upon in the literature (reviewed in Smith, 1996; Kunugi et al., 2010), thus far there is limited evidence that indicates a role for altered BDNF function in contributing to the damaging eﬀects of GCs. In this regard it is important to understand the regulation of BDNF and its signaling pathway by GCs. For the purpose of our review, we explore the relationship between GCs and the BDNF pathway, with a view to addressing whether alterations in BDNF signaling may serve to mediate eﬀects of GCs, in particular within the hippocampus.

GLUCOCORTICOIDS Exposure to stress activates the hypothalamo– pituitary–adrenal (HPA) axis. Physiological and psychological stressors strongly activate the paraventricular nucleus (PVN) of the hypothalamus, via activatory inputs from brain stem nuclei and the amygdala resulting in the release of corticotrophin-releasing hormone (CRH) (reviewed in Jankord and Herman, 2008). CRH circulating through the hypophyseal portal system, acts on the pituitary, inducing the release of adrenocorticotrophic hormone (ACTH) which promotes GC release from the adrenal cortex (reviewed in Herman and Cullinan, 1997). GCs are adrenal cortex-derived

steroid hormones, predominant among which are cortisol in humans and corticosterone in rodents. Classically, GCs mediate their responses via the type I mineralocorticoid receptor (MR) and the type II glucocorticoid receptor (GR) (reviewed in De Kloet et al., 2005). MR has a high aﬃnity for corticosterone, as well as aldosterone, whereas GR has a higher aﬃnity for dexamethasone and an approximately 10-fold lower aﬃnity than MR for corticosterone (Reul and de Kloet, 1985). On ligand binding, GC receptors undergo conformational changes and translocate to the nucleus, where they bind to their consensus sequences, the glucocorticoid response elements (GREs) as homo(Beato, 1989) or hetero-dimers (Trapp et al., 1994), thus triggering transcription of target genes (reviewed in Zanchi et al., 2010). GC receptors can also bind negative GREs, thus repressing the transcription of genes primarily by two mechanisms, namely by competition for binding with a transcription factor at an overlapping binding site, or by interaction with adjacent transcription factors to impede their action (reviewed in Dostert and Heinzel, 2004). Stimulation of GC receptors has been linked to discrete physiological outcomes, suggesting that the speciﬁc receptor recruited, or the stoichiometry of GC receptors stimulated, may evoke distinct functional consequences (reviewed in De Kloet and Derijk, 2004). The diﬀering aﬃnity of GC receptors, as well as the tissue-speciﬁc stoichiometric expression of the GR and MRs, is hypothesized to endow neuronal cells with a wide dynamic range of potential biochemical outcomes mediated through the regulation of diﬀerent GC-responsive target genes (reviewed in De Kloet and Derijk, 2004). While the classical view of GC action is through relatively slow-onset genomic eﬀects, it is important to note that speciﬁc eﬀects of GCs, including their eﬀects on the hypothalamic release of CRH (reviewed in Dallman, 2005), rapid eﬀects on behavior (Oitzl and de Kloet, 1992; Kruk et al., 2004) and cellular excitability (Karst et al., 2005), often occur across a time frame of a few seconds or minutes indicating likely nongenomic action. The fast actions of GCs could involve a role for cytoplasmic MR and GR monomer interactions with cytoplasmic proteins (reviewed in Dostert and Heinzel, 2004), or could be through membrane GC receptors (reviewed in Losel and Wehling, 2003). Studies have indicated the presence of plasma membrane-associated putative GC receptors that on binding the ligand inﬂuence a pertussis toxin (PTX)sensitive G-protein-coupled pathway linked to protein kinase C (PKC) (reviewed in Losel and Wehling, 2003). GCs act to aid the body in coping with the demands imposed by stress exposure, mobilizing energy stores, and suppressing non-vital body functions such as inﬂammatory responses and reproduction (reviewed in Sapolsky et al., 2000). In addition, GCs also perform the crucial task of negative feedback regulation of the HPA axis, thus preventing the uncontrolled activation of the stress response. Feedback regulation occurs not only at the level of the hypothalamus and the pituitary, but also via multiple other cortical and subcortical structures (reviewed in Herman et al., 2003). In particular, the

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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hippocampus is one of the crucial sites in the brain implicated in mediating feedback control of the HPA axis (reviewed in Herman et al., 2003). While the high-aﬃnity MR is largely expressed in limbic areas like the hippocampus, lateral septum and the amygdala, the low-aﬃnity GR is more ubiquitously present (Reul and de Kloet, 1985). MR is generally saturated under basal GC levels (Arriza et al., 1988), whereas under conditions of stress-induced elevation of GCs or at circadian peaks the low-aﬃnity GR receptor is recruited (Kitchener et al., 2004) and plays a crucial role in many of the stress-associated neurological eﬀects observed. The hippocampus harbors a high density of both the MR and GR receptors, which on binding GCs repress the hypothalamic release of CRH via multi-synaptic inputs (Radley and Sawchenko, 2011). Under conditions of prolonged stress, the ensuing persistent elevation of GCs, often in conjugation with excitatory amino acids, can mediate a variety of adverse structural and cellular changes including dendritic atrophy and neuronal damage in the hippocampus (Sapolsky et al., 1990; Haynes et al., 2004, reviewed in Fuchs et al., 2001), which may potentially compromise hippocampal function. Prolonged elevation of GC levels evokes extensive cellular damage and loss in hippocampal CA subﬁelds, including cell layer irregularity, soma shrinkage/ condensation, nuclear pyknosis and dendritic atrophy of CA3 pyramidal neurons (Sapolsky et al., 1990; Haynes et al., 2004). Strikingly, hippocampal dentate gyrus (DG) granule cell neurons do not appear to be as susceptible to the damaging eﬀects of sustained GC exposure (Uno et al., 1989; Sapolsky et al., 1990). However, loss of circulating GCs by adrenalectomy (ADX) evokes extensive cell death of the mature granule cell neurons in the DG (Sloviter et al., 1989; Cameron and Gould, 1994), but is known to enhance proliferation of progenitors within the subgranular zone (SGZ) of the DG subﬁeld (Cameron and Gould, 1994). Further, chronic GC exposure negatively regulates adult hippocampal neurogenesis by reducing the proliferative rate of hippocampal progenitors (Cameron and Gould, 1994). The eﬀects of GCs on cell proliferation, dendritic architecture and neuronal survival vary across distinct hippocampal cellular populations. GCs by disrupting hippocampal glucose utilization (Virgin et al., 1991) are also hypothesized to render neurons vulnerable to metabolic (Lawrence and Sapolsky, 1994) and excitotoxic (Roy and Sapolsky, 2003) insults. In addition, GCs mediate robust eﬀects on hippocampal cellular excitability with a bimodal eﬀect of GCs on LTP, with both ADX and exposure to high GC levels impairing hippocampal LTP (Pavlides et al., 1993). Persistently elevated GC levels also lower the expression of GRs in the hippocampus (Kitchener et al., 2004), thus further impairing feedback response and resulting in a selfsustaining cycle of HPA axis dysregulation. Several previous reviews (Joe¨ls, 2008; Conrad, 2008) have focused on the consequences of short- and long-term GC administration on neuronal damage, dendritic atrophy and functional plasticity, primarily within limbic neurocircuitry and in the context of chronic stress. For

the purposes of this review we have chosen to restrict ourselves to examining the literature that links GCs to the regulation of the neurotrophin BDNF, and its potential contribution to the eﬀects of GCs.

BDNF BDNF is the most abundantly expressed member of the nerve growth factor family, referred to as the neurotrophins. Neurotrophins are known to exert a powerful inﬂuence on development (reviewed in Bernd, 2008), survival (reviewed in Lipsky and Marini, 2007) and plasticity (Causing et al., 1997; Bergami et al., 2008) of neurons within the immature and adult nervous system. The Bdnf gene has a complex structure with multiple exons, each with their individual promoters, which are alternatively spliced to generate exon-speciﬁc Bdnf transcript variants with one common Bdnf coding exon (Aid et al., 2007). The Bdnf gene has been characterized in the mouse, rat and human (Liu et al., 2005; Aid et al., 2007). In the rat, the Bdnf gene through the alternate splicing of eight distinct non-coding 50 exons (I–VIII) to a common 30 exon (IX) can generate multiple exon-speciﬁc Bdnf transcripts. Each 50 untranslated exon has a unique promoter, while the common 30 exon (IX) is responsible for coding the mature BDNF protein. BDNF mediates its eﬀects by binding to its receptor tropomyosin-related kinase B (TrkB), and through the activation of signaling cascades, predominant among which are Ras-Raf-MEK (MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase)) kinase, phospholipase C-c (PLCc) and the phosphatidylinositol-3-kinase–Akt (v-akt murine thymoma viral oncogene homolog) (PI3–Akt) pathways (Chao, 2003; Reichardt, 2006). The activation of these signaling pathways culminates in target protein phosphorylation, and thus functional modulation of downstream molecules involved in vesicular mobility, glutamatergic neurotransmission and neurotransmitter release (reviewed in Yoshii and Constantine-Paton, 2010). BDNF can also interact with the low-aﬃnity p75 neurotrophin receptor (p75NTR) (Fayard et al., 2005), which is a member of the tumor necrosis receptor family. Several diﬀerent pathways including the c-Jun N-terminal kinase (JNK) signaling cascade, nuclear factor-jB (NF-jB) activation, ceramide signaling and Rho family GTPase activation lie downstream of ligand-mediated activation of p75NTR (reviewed in Roux and Barker, 2002; Reichardt, 2006). Interestingly, there are several points for crosstalk between the TrkB and p75NTR cascades (Bibel et al., 1999), and often neurotrophin-mediated eﬀects through these two pathways exert opposing actions (reviewed in Miller and Kaplan, 2001). For example, TrkB receptor activation almost always promotes neuronal survival and diﬀerentiation (review Barnabe´-Heider and Miller, 2003), while the engagement of p75NTR frequently, but not invariably, promotes apoptosis (Lee et al., 2001; Teng et al., 2005). In the hippocampus in particular, BDNF is robustly expressed and released in response to activity and plays an important role in activity-dependent sculpting

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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and reﬁnement of synapses, and in the enhancement of synapse number and density (reviewed in Kuczewski et al., 2009). Cellular excitability itself is potentiated by BDNF through the enhancement of presynaptic vesicle release (Jovanovic et al., 2000) and postsynaptic glutamatergic currents (Kovalchuk et al., 2002). A form of cellular plasticity strongly inﬂuenced by BDNF signaling is adult hippocampal neurogenesis, where BDNF acts to promote the birth (Lee et al., 2002; Scharfman et al., 2005), survival (Sairanen et al., 2005) and maturation (Chan et al., 2008; Bergami et al., 2008) of new neurons in the hippocampal neurogenic niche. BDNF expression is modulated by stress (Tsankova et al., 2006; Nair et al., 2007; Zhang et al., 2010), and has been implicated in the pathophysiology of mood disorders (reviewed in Duman and Monteggia, 2006), and in the mechanism of action of antidepressant agents (Li et al., 2008). Studies have demonstrated that direct BDNF infusion into the hippocampus enhances cellular excitability, and when accompanied by a weak stimulus induces robust LTP (Figurov et al., 1996), widely considered to be the cellular correlate of memory. BDNF eﬀects on LTP are correlated with an improvement in performance on hippocampal-dependent learning tasks (Cirulli et al., 2004). Conversely, a loss of BDNF signaling in the hippocampus results in dampened LTP, as well as impairments in cognitive function (Minichiello et al., 1999). BDNF plays a pivotal role in the modulation of structural and synaptic plasticity (reviewed in Yoshii and Constantine-Paton, 2010), as well as mood (Duman and Monteggia, 2006) and memory (reviewed in Tyler et al., 2002), and its expression is strongly regulated by diverse external stimuli that are known to inﬂuence these parameters (reviewed in Tardito et al., 2006).

REGULATION OF BDNF The regulation of BDNF expression and signaling occurs at multiple levels (Fig. 1), from transcriptional control of the distinct exon-speciﬁc Bdnf transcripts to sortilindependent modulation of BDNF traﬃcking. The complex gene structure of Bdnf allows exon-speciﬁc Bdnf promoters to be diﬀerentially recruited by distinct transcription factors both under basal conditions, and in response to stimuli (Timmusk et al., 1995; Tao et al., 2002; Dias et al., 2003). While the Bdnf gene has been relatively well characterized, an in-depth analysis of the distinct transcription factors that combinatorially control the regulation of the multiple Bdnf transcript variants is still limited. The best understanding currently exists for the role of cyclic AMP response element-binding protein (CREB) (Tao et al., 1998), upstream stimulatory factors, calcium response factors (Shieh et al., 1998; Tao et al., 2002) and the transcriptional repressor methylCpG-binding protein 2 (MeCP2) (Chen et al., 2003), in the regulation of the expression of speciﬁc Bdnf transcript variants. In addition to the usage of multiple promoters, the Bdnf gene also has two alternate polyadenylation sites (Timmusk et al., 1993), which further add to the diversity of Bdnf transcripts through the

formation of either the long or short 30 UTR form of the speciﬁc Bdnf transcript. It has been hypothesized that the complex architecture of the Bdnf gene may endow neuronal cells with the ability to diﬀerentially target select Bdnf transcripts to speciﬁc cellular locations (Chiaruttini et al., 2008; Baj et al., 2012), and modulate their stimulus-responsivity and translatability (Lauterborn et al., 1996; Tao et al., 2002). The evidence of RNAbinding proteins that contribute to the diﬀerential localization of speciﬁc Bdnf mRNA variants is currently limited, with a role thus far indicated for the RNA-binding protein translin in dendritic traﬃcking of Bdnf transcripts (Chiaruttini et al., 2009; Wu et al., 2011). Transcriptional control of Bdnf expression through the recruitment of distinct promoters and usage of diﬀerent polyadenylation sites could inﬂuence Bdnf mRNA stability, translatability and the kinetics of stimuli-responsivity, thus providing the possibility of powerful control in the modulation of the expression of this key neurotrophin. In addition to the transcriptional regulation of Bdnf expression, regulation of BDNF can also occur at the level of BDNF synthesis, traﬃcking, secretion and processing (Fig. 1). Bdnf transcripts with the long versus short 30 UTRs diﬀerentially inﬂuence the translatability and stability of Bdnf mRNA (Fukuchi and Tsuda, 2010). Short 30 UTR Bdnf transcripts are linked to basal BDNF synthesis and the long 30 UTR Bdnf mRNAs have been associated with rapid, activity-responsive translation (Lau et al., 2010) which can be spatially restricted, for example to active dendrites (An et al., 2008; Oe and Yoneda, 2010). BDNF is a secreted protein, which is synthesized as pro-BDNF and then undergoes further proteolytic processing to form mature BDNF (Seidah et al., 1996; Lu, 2003). Pro-BDNF traﬃcking occurs primarily through the regulated secretory pathway, which can be strongly inﬂuenced by signaling cascades (Goodman et al., 1996; Kru¨ttgen et al., 1998; reviewed in Thomas and Davies, 2005). The traﬃcking of proBDNF into the regulated secretory pathway undergoe modulation by the intracellular chaperone sortilin and by carboxypeptidase E (Chen et al., 2005). Neuronal cells are capable of secretion of both processed mature BDNF, as well as the precursor pro-BDNF (Yang et al., 2009). Conversion of pro-BDNF to BDNF is mediated via furin and prohormone convertases (PC) within cells (Seidah et al., 1996), and extracellularly through the plasmin–tissue plasminogen activator (tPA) system (Lee et al., 2001) and matrix metalloproteinases (MMPs) (Lee et al., 2001; Hwang et al., 2005). Pro-BDNF can bind to p75NTR (Fayard et al., 2005) and induce signaling (reviewed in Roux and Barker, 2002; Reichardt, 2006). Regulation at the level of intracellular and extracellular proteolytic processing of BDNF could provide for powerful control of the consequences of BDNF signaling on neuronal survival and cellular excitability (reviewed in Chao and Bothwell, 2002). Regulation of BDNF signaling could also occur through a modulation of the expression and alternate splicing, translation and traﬃcking of the TrkB and p75NTRs, and through the regulation of their downstream signaling cascades and interactions with intracellular adaptor

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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Fig. 1. The regulation of brain-derived neurotrophic factor (BDNF) synthesis, processing, traﬃcking, secretion and signaling by glucocorticoids (GCs). The regulation of BDNF synthesis and function by GC can occur at multiple levels, from transcriptional control of the distinct exon-specﬁc Bdnf transcripts to signaling at the postsynaptic neuron. (1) Bdnf transcription can be modulated by GCs either by direct binding to putative glucocorticoid response elements (GREs) present on the promoter regions or by interfering with the activity of other transcription factors reported to contribute to Bdnf transcription, such as the activator protein-1 (AP-1) complex and CREB. (2) In addition to the transcriptional regulation of Bdnf, glucocorticoids can also potentially alter the translation of the Bdnf gene by modulating the activity of the translational machinery. (3) BDNF is a secreted protein, which is synthesized as pro-BDNF and then undergoes proteolytic processing to form the mature BDNF protein. Conversion of pro-BDNF to mature BDNF is mediated via multiple intracellular and extracellular proteases including furin and prohormone convertases (PC) within cells, and the plasmin–tissue plasminogen activator (tPA) system and matrix metalloproteinases (MMPs) extracellularly. GCs can modulate the levels or the activity of the intracellular and extracellular proteases and thus regulate the levels of available mature BDNF. (4) Mature BDNF binds to intracellular chaperones which allow sorting of BDNF to regulated secretory pathway or the constitutive pathway. Pro and mature-BDNF are packaged and traﬃcked either to the dendrites or axons. (5) BDNF is released in response to activity and post-synaptically interacts with its cognate receptor tropomyosin-related kinase B (TrkB) or the low-aﬃnity receptor p75NTR to activate distinct signaling cascades. (6) BDNF binding to TrkB, activates the MAPK (mitogen-activated protein kinase) pathway, phospholipase C-c (PLCc) and the phosphatidylinositol-3-kinase (PI3-kinase) pathways. The activation of these signaling pathways culminates in functional modulation of downstream target molecules involved in synaptic plasticity, neuronal survival and cellular excitability. GCs potentially modulate the activity of these signaling pathways at multiple levels. GCs prevent TrkB interactions with speciﬁc adaptor proteins such as Shp2 thus impairing activation of the MAP kinase pathway. Further, GCs promote the transcription of MAP kinase inhibitor protein MAP kinase phosphatase 1 (MKP 1) which serves to terminate MAP kinase signaling. In addition, GCs also impair TrkB and glucocorticoid receptor (GR) interaction, thus attenuating PLCc pathway activation. Given is a symbolic representation of mature BDNF (mBDNF), pro BDNF, GR, GC, p75 NTR and TrkB. Red circles denote sites in the BDNF synthesis, processing or signaling pathway which are potential direct targets for the modulatory eﬀects of GCs on the BDNF pathway. Red question marks denote putative targets for GC modulation of the BDNF pathway based on indirect evidence of reported eﬀects of GCs in other systems.

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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proteins (Fig. 1). TrkB exists as both the catalytic fulllength variant (TrkB.FL) and the alternatively spliced truncated forms (TrkB.T1 and T2) (Fryer et al., 1996; Strohmaier et al., 1996), which lack the tyrosine kinase domain, and have been suggested to exert a dominant negative role (Eide et al., 1996). Evidence also indicates that truncated TrkB forms may signal through distinct pathways, for example by the modulation of inositol1,4,5-trisphosphate-dependent calcium release, and through extracellular or intramembrane interactions with p75NTR (Baxter et al., 1997; Rose et al., 2003; Michaelsen et al., 2010). Modulation of the balance of full-length versus truncated TrkB expression could evoke distinct biochemical and functional outcomes of BDNF signaling (Sherrard et al., 2009; Vidaurre et al., 2012). The regulation of BDNF occurs both at the transcriptional and posttranscriptional levels providing multiple sites of action through which GCs may modulate BDNF expression and signaling (Fig. 1).

GLUCOCORTICOID REGULATION OF BDNF EXPRESSION Inﬂuence of glucocorticoids on Bdnf transcription Several studies (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001) have examined the consequences of systemic administration with the GCs corticosterone and dexamethasone, on the expression of Bdnf mRNA within multiple brain regions, predominantly focusing on the hippocampus. Corticosterone has been shown to decrease the levels of Bdnf mRNA in the hippocampal DG subﬁeld following either acute (2–8 h) (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001) or chronic (7 days) (Smith et al., 1995b) administration. Decreased Bdnf mRNA levels within the hippocampal subﬁelds following acute corticosterone treatment are observed fairly rapidly (Schaaf et al., 1998), and are accompanied by a decrease in hippocampal BDNF protein levels (Schaaf et al., 1998). Decreased Bdnf mRNA levels have also been noted following treatment with dexamethasone (21 days) in the frontal cortex and hippocampus (Dwivedi et al., 2006). While most studies have shown a decline in hippocampal Bdnf mRNA expression following GC administration (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001), results diﬀer in the hippocampal subﬁelds in which changes in Bdnf mRNA were noted. These discrepancies may be a consequence of diﬀerences in the animal models used, time points examined or in corticosterone dose. Further, a history of prior GC exposure may signiﬁcantly alter responses to future GC exposure, as has been suggested by reports of a downregulation of cortical Bdnf mRNA expression on acute exposure to corticosterone 14 days following chronic corticosterone treatment (Gourley et al., 2009). Strikingly, the developmental time-point examined appears to dramatically inﬂuence the nature of the GC regulation of Bdnf, with no change in hippocampal Bdnf expression

following early postnatal treatment (Roskoden et al., 2004) and a signiﬁcant decline in response to adult-onset treatment (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001; Dwivedi et al., 2006). However, most studies have largely looked at the immediate consequences of GC treatment on Bdnf expression, and have not addressed whether GC exposure may evoke slow-emerging but persistent changes in Bdnf expression. Intriguingly, a few studies have demonstrated that a history of prenatal dexamethasone exposure induced a decline in cortical and hippocampal basal Bdnf mRNA in juvenile animals (Nagano et al., 2012), and altered the stimulus-evoked regulation of Bdnf exon IV expression (Hossain et al., 2008). This raises the interesting possibility that the eﬀects of early GC treatment may only manifest at later ages. The in vivo repressive eﬀects of GCs on Bdnf expression have also been corroborated in studies using in vitro models (Kino et al., 2010). Dexamethasone has been shown to suppress Bdnf mRNA and protein expression in rat cortical neuronal cells, whereas the endogenous glucocorticoid corticosterone showed a biphasic eﬀect (Kino et al., 2010). In contrast to the emerging consensus from several reports that GCs reduce Bdnf mRNA expression in both cortical (Dwivedi et al., 2006; Gourley et al., 2009) and hippocampal brain regions (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001), the eﬀects of ADX have been far less consistent (Barbany and Persson, 1992, 1993; Chao and McEwen, 1994; Smith et al., 1995b; Lauterborn et al., 1998). Speciﬁc studies have shown a signiﬁcant downregulation of cortical and hippocampal Bdnf expression following ADX (Barbany and Persson, 1992, 1993) which can be rescued by dexamethasone treatment (Barbany and Persson, 1992). However, there are contradictory studies that indicate no change in Bdnf expression in these brain regions (Lauterborn et al., 1995; Smith et al., 1995b; Vaidya et al., 1997), and a few reports that indicate an opposing upregulation of BDNF mRNA following ADX (Chao and McEwen, 1994; Lauterborn et al., 1998). These discrepancies are diﬃcult to resolve since most studies have examined Bdnf expression using in situ hybridization or real-time PCR, similar time-points after ADX, and predominantly in rat models. However, all the reports that indicate ADX-evoked changes in hippocampal basal Bdnf mRNA levels report only relatively small hippocampal subﬁeld-speciﬁc eﬀects (Chao and McEwen, 1994; Lauterborn et al., 1998), hinting at the possibility that the GCs may not exert a strong tonic control on basal Bdnf mRNA expression. It is possible that the eﬀects of ADX may only be unmasked in the context of stimulus-responsive Bdnf mRNA regulation. ADX animals exhibit a robust potentiation of the activity-mediated Bdnf mRNA upregulation in the hippocampus in paroxysmal after discharge or hilus lesion models (Lauterborn et al., 1995, 1998). In contrast, ADX attenuates the eﬀects of kainate treatment on Bdnf mRNA expression (Barbany and Persson, 1992). In

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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summary, the current literature provides support for the notion that the absence of circulating GCs may not exert a strong eﬀect on basal Bdnf expression, but may alter the stimulus-responsivity of Bdnf promoters. Further, elevated circulating GCs appear to predominantly cause a robust downregulation of Bdnf transcript levels in cortical and hippocampal brain regions (Fig. 1(1)). Inﬂuence of glucocorticoids on exon-speciﬁc Bdnf transcript variants Though a detailed mechanistic understanding of how GCs inﬂuence speciﬁc Bdnf promoters is missing, several studies have demonstrated basal and stimulus-evoked alterations in Bdnf exon II and VI-containing transcripts by GCs (Dwivedi et al., 2006; Hansson et al., 2006). It is noteworthy that the Bdnf VI promoter contains a putative GRE (Fig. 1(1)) (Benraiss et al., 2001), which could allow for the possibility of direct genomic eﬀects of GCs on Bdnf transcription through this speciﬁc Bdnf promoter. However, thus far no experiments have systematically addressed the role of GR or MR-mediated regulation of the Bdnf VI promoter GRE, and its contribution to basal or GC-mediated regulation of Bdnf expression. In addition to possible direct GRE-mediated transcriptional eﬀects, GCs could also inﬂuence Bdnf expression by modulation of the activity of other transcription factors reported to contribute to Bdnf mRNA regulation, such as the activator protein-1 (AP-1) complex and CREB (reviewed in Kassel and Herrlich, 2007). Ligand bound GR has been suggested to repress AP-1-mediated transcriptional activation by c-Jun-containing AP-1 complexes (Unlap and Jope, 1994; Diefenbacher et al., 2008). Given that the Bdnf gene has a high density of AP-1-binding sites (Hayes et al., 1997), this raises the possibility that GC exposure may serve to repress AP-1-mediated increases in Bdnf expression. It has also been reported that GR and CREB show mutual interference of transcriptional activity (Stauber et al., 1992). Since CREB has been demonstrated to be an important regulator of Bdnf expression primarily via Bdnf promoters I and IV (Shieh et al., 1998; Tao et al., 1998), it is possible to speculate that elevated GC levels could inﬂuence the CREBmediated transcriptional regulation of Bdnf expression (Fig. 1(1)). These ideas are still relatively nascent, and require experimental evidence to demonstrate their validity. Such experiments are important because they could provide a mechanistic understanding of how GC perturbations inﬂuence the regulation of important target genes, including Bdnf, through interaction with key plasticity-associated transcription factors/complexes like CREB and AP-1. Inﬂuence of glucocorticoids on Bdnf mRNA stability Several studies have examined changes in Bdnf mRNA levels following GC exposure (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001). It has been suggested that changes in Bdnf mRNA expression levels predominantly arise as a consequence of altered transcription rather than through possible changes in mRNA stability. Experimental evidence however for this

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idea is currently limited, and possible eﬀects of GCs on both transcription and degradation of Bdnf mRNAs still need to be tested. It is unknown whether the stability of Bdnf transcript isoforms, containing either the short or the long 30 UTR, is altered by GC exposure. It is of interest to note that GCs have been shown to inﬂuence the stability of speciﬁc mRNAs including preproglucagon (Zhang et al., 2009) and CRH (Ma et al., 2001), suggesting that in addition to their well-studied transcriptional eﬀects, GCs may also regulate mRNA levels by modulation of mRNA degradation. Inﬂuence of glucocorticoids on BDNF translation, processing, traﬃcking and secretion In addition to the eﬀects at the level of Bdnf mRNA, GCs could also inﬂuence BDNF synthesis, secretion and processing (Fig. 1), however this has not been clearly addressed experimentally. GCs have been reported to inhibit speciﬁc components of protein translation complexes inﬂuencing the rate of translation initiation and protein synthesis (Shah et al., 2000), a role suggested to mediate some of their catabolic eﬀects. Although GCs have been shown to inﬂuence the translation of several proteins, GC-evoked decline in BDNF protein levels has largely been attributed to be the consequence of decreased Bdnf transcript expression (Schaaf et al., 1998). It is also possible that GCs may regulate BDNF by inﬂuencing its secretion. GCs are known to regulate speciﬁc molecules that inﬂuence exocytosis such as annexin A1 (John et al., 2006; McArthur et al., 2009), which is reported to be a potent inhibitor of regulated exocytosis. However, to the best of our knowledge no experiments thus far have addressed whether the traﬃcking of BDNF in the secretory pathway, and its eventual release are modulated by GCs. BDNF undergoes proteolytic processing by intracellular enzymes collectively termed PC including PC1/2 and furin (Seidah et al., 1996), and in the extracellular space is processed by the plasmin–tPA system (Lee et al., 2001; Pang et al., 2004) and MMPs (Lee et al., 2001; Hwang et al., 2005) (Fig. 1(3)). Intriguing reports that corticosterone transcriptionally represses PC1 expression in the PVN (Dong et al., 1997), and that GCs impede plasmin function by inhibiting the plasminogen activator (Gelehrter et al., 1987) raise the possibility that BDNF processing may also be a possible target of GCs (Fig. 1(3)). The importance of regulation of BDNF traﬃcking has clearly emerged from studies demonstrating that BDNF polymorphisms (BDNFVal66Met) alter the regulated, in particular activity-dependent, secretion of BDNF (Egan et al., 2003) through perturbation of proBDNF–sortilin interaction (Chen et al., 2004), which could evoke diﬀerential functional outcomes (Chen et al., 2006). The above studies provide further impetus to address whether GCs can inﬂuence the traﬃcking and transport of BDNF, thus regulating BDNF secretion and function. Stress regulation of BDNF Exposure to acute or chronic stress is a physiological state in which enhanced levels of circulating GCs are

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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observed. While the purpose of this review is not to exhaustively cover studies that have examined the stress regulation of BDNF, we will compare and contrast some of the key changes observed in BDNF following stress with the results obtained following GC administration. It has been demonstrated by several studies that exposure to a variety of stressors both acute (single stress exposure, (2–8 h)) (Smith et al., 1995a; Ueyama et al., 1997; Lee et al., 2008) and chronic (10 days to 6 weeks) (Murakami et al., 2005; Tsankova et al., 2006; Nair et al., 2007; Rothman et al., 2012) can signiﬁcantly downregulate both Bdnf mRNA expression and protein levels in the hippocampus. This decrease in Bdnf expression is seen predominantly in the DG and CA3 hippocampal subﬁelds (Smith et al., 1995a; Murakami et al., 2005). However, the duration of stress diﬀerentially inﬂuences Bdnf expression with short-duration stressors of less than 60 min evoking an induction in hippocampal Bdnf expression and protein levels (Marmige`re et al., 2003; Molteni et al., 2009; Neeley et al., 2011). Overall, the evidence suggests that the eﬀects of stress and GC exposure on Bdnf expression are similar within the hippocampus. In contrast, stress has been shown to cause an increase in Bdnf expression in the frontal cortex (Bland et al., 2005; Lee et al., 2006; Fanous et al., 2010), PVN (Smith et al., 1995a) and amygdala (Fanous et al., 2010; Lakshminarasimhan and Chattarji, 2012). This diﬀers from reports following GC administration, which is largely associated with a decline in Bdnf expression in cortical brain regions, including the frontal cortex (Dwivedi et al., 2006; Gourley et al., 2009). The role of GCs in mediating the eﬀects of stress on Bdnf expression has often been suggested, though few direct studies have addressed this experimentally. In ADX animals, the acute stress-mediated downregulation of Bdnf expression in the DG and CA3 hippocampal subﬁelds is prevented (Smith et al., 1995b). However, restoration of basal levels of circulating corticosterone in ADX animals restores the stress-mediated repression of Bdnf expression (Smith et al., 1995b). These results suggest that basal circulating GCs are required for the eﬀects of stress on hippocampal Bdnf expression. However, stress eﬀects on Bdnf mRNA expression were observed in those ADX animals maintained on basal corticosterone but incapable of showing the stressmediated spike in circulating GCs. These studies support a role for additional factors in contributing to the eﬀects of stress on hippocampal Bdnf expression.

GLUCOCORTICOID RECEPTORS AND BDNF While many studies have examined whether changes in circulating GCs alter BDNF expression, relatively a few reports have explored the contribution of the GC receptors MR and GR to the regulation of BDNF (Chao and McEwen, 1994; Hansson et al., 2000; Kino et al., 2010). Pharmacological and genetic strategies (reviewed in Kolber et al., 2008; Arnett et al., 2011) targeting the GC receptors, provide powerful tools to address the contribution of GC receptors to BDNF regulation. In vitro

pharmacological studies demonstrated that aldosterone which has a higher aﬃnity for the MR receptor increased Bdnf mRNA and protein levels in cultured cortical neurons, whereas dexamethasone which has a higher aﬃnity for GR evoked a decline in Bdnf mRNA and protein (Kino et al., 2010). The role of GRs and MRs in the regulation of BDNF has also been examined in a study where ADX animals received corticosterone, aldosterone or RU28362, the synthetic GR agonist (Chao and McEwen, 1994). These studies (Chao and McEwen, 1994; Hansson et al., 2000; Kino et al., 2010) indicate that ligands for both MR and GR regulate hippocampal BDNF expression. However, treatment with the MR antagonists spironolactone (McCullers and Herman, 1998) or eplerenone (Hlavacova et al., 2010) does not appear to alter basal hippocampal Bdnf expression. These studies raise the possibility of diﬀerential eﬀects of MR and GR on BDNF expression. Diﬀerential eﬀects of GC receptors on BDNF are particularly relevant while considering the results of sustained GC exposure on BDNF, since the dose range utilized in most studies (Barbany and Persson, 1992; Smith et al., 1995b; Schaaf et al., 1997, 1998; Hansson et al., 2000, 2006; Vellucci et al., 2001) suggests a likely recruitment of GR to mediate the GC-evoked decline in BDNF. However, these possibilities need to be carefully examined by addressing whether the eﬀects of chronic GC treatment are blocked by administration of selective GR or MR antagonists, and to address whether these GC receptors exert diﬀerential eﬀects on BDNF in a region-speciﬁc manner. Many diﬀerent GR and MR mutants have been generated (reviewed in Kolber et al., 2008; Arnett et al., 2011), including total and forebrain-selective (Boyle et al., 2005) knockouts, total (Ridder et al., 2005) and forebrain-selective (Wei et al., 2004) overexpressor mutants and DNA-binding mutants (Reichardt et al., 2000). While the focus of most studies with GR and MR mutants has been to examine HPA axis regulation, stress-responsivity and mood-related behavior (reviewed in Kolber et al., 2008), a few studies (Ridder et al., 2005; Molteni et al., 2010; Alboni et al., 2011) have addressed molecular changes including regulation of BDNF. GR (+/) heterozygous mice have been reported to show either no change in basal Bdnf mRNA (Molteni et al., 2010), or a reduction in BDNF protein levels in the hippocampus (Ridder et al., 2005), but exhibit an upregulation in the frontal and parietal cortex (Schulte-Herbru¨ggen et al., 2007; Molteni et al., 2010), and the hypothalamus (Schulte-Herbru¨ggen et al., 2007). The induction of Bdnf expression in the hypothalamus of GR+/ mice was also observed in conditional GR mutants (GRﬂox/+;Sim1Cre+) with a loss of GR restricted to the PVN (Jeanneteau et al., 2012). Further, reports from GR-impaired (GR-i) mice bearing a hypothalamic GR antisense RNA have demonstrated lower hippocampal expression of Bdnf IV mRNA and total Bdnf mRNA levels (Alboni et al., 2011). Such a decline in hippocampal Bdnf expression could also be secondary to alterations in circulating GC levels. Studies with GR-overexpressing mice indicated increased

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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hippocampal (Ridder et al., 2005) and amygdaloid (Schulte-Herbru¨ggen et al., 2006) BDNF expression. A caveat to keep in mind prior to interpretation of the molecular changes observed in GR mutants is whether changes in BDNF are a direct consequences of GR perturbation within the brain region examined, or secondary to alteration in circulating hormones, stressresponsivity and behavior (reviewed in Kolber et al., 2008). Future studies with conditional GR and MR mutants that restrict the genetic perturbation spatiotemporally would provide important insights into the manner in which GC receptors modulate BDNF expression and signaling.

GLUCOCORTICOID REGULATION OF BDNF SIGNALING In addition to the regulation of BDNF mRNA and protein expression, GCs could impinge on BDNF signaling through modulation of the TrkB and P75NTR receptors, and their downstream cascades (Fig. 1(6)). Long-term treatment with corticosterone for 3–7 weeks caused a decline in TrkB protein, but not trkB mRNA levels in the frontal cortex and the hippocampus (Kutiyanawalla et al., 2011). However, it is important to note that the eﬀects of corticosterone treatment may be age dependent. Adult rodents exhibited either no change, or an enhancement in trkB mRNA (Schaaf et al., 1997; Vellucci et al., 2001, 2002) but did not show a reduction in protein levels following chronic corticosterone administration (Kutiyanawalla et al., 2011), whereas postnatal rats showed a gradually emerging but robust increase in trkB mRNA levels in the hippocampus following corticosterone treatment from postnatal day 1 to 12 (Roskoden et al., 2004). However, ADX does not appear to change the basal expression of trkB mRNA in the adult hippocampus (Barbany and Persson, 1993). Thus far the eﬀects of corticosterone on trkB expression in the aged brain are unknown. In this regard it is interesting to note that chronic mild repeated stress evoked a signiﬁcant increase in trkB mRNA expression in the hippocampus of both young and aged animals (Shao et al., 2010). Further, acute stress has been shown to enhance hippocampal trkB mRNA expression (Shi et al., 2010) but also evokes a rapid downregulation of trkB transcript expression in the pituitary suggesting spatiotemporal diﬀerences in trkB transcriptional regulation following stress (Givalois et al., 2001). While most studies have examined the eﬀects of GCs on the catalytic TrkB.FL (Barbany and Persson, 1993; Schaaf et al., 1997; Vellucci et al., 2001; Roskoden et al., 2004), a few studies thus far have addressed whether corticosterone or stress diﬀerentially inﬂuences trkB transcript variants (Vellucci et al., 2002; Shao et al., 2010). Chronic dexamethasone treatment for 5 days induced an increase in truncated trkB transcript expression with no eﬀects noted on trkB.FL expression (Vellucci et al., 2002). Longer duration corticosterone treatment also did not alter hippocampal catalytic trkB expression (Kutiyanawalla et al., 2011). It has been shown that chronic, but not acute,

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immobilization stress (Nibuya et al., 1999) and chronic unpredictable stress (Shao et al., 2010) enhanced catalytic trkB.FL mRNA expression, without inﬂuencing the expression of the truncated trkB mRNA transcripts. Unlike chronic stress, which appears to predominantly enhance hippocampal trkB mRNA expression (Nibuya et al., 1999; Li et al., 2007; Shao et al., 2010; Shi et al., 2010), relatively sustained corticosterone treatment has been largely associated with a decline in TrkB protein levels but no major changes in trkB mRNA expression (Kutiyanawalla et al., 2011). This suggests that the eﬀects of stress on hippocampal trkB expression are unlikely to be mediated via corticosterone. A systematic characterization of the eﬀects of GCs on the alternative splicing of the trkB transcripts has not been carried out. Further, an important question that is relatively unexplored is the inﬂuence of GCs on p75NTR expression. GCs could powerfully alter BDNF signaling by inﬂuencing the stoichiometry of the catalytic and truncated TrkB receptor, and the low-aﬃnity p75NTR. While GCs have thus far not been shown to inﬂuence TrkB receptor traﬃcking, intriguing reports indicate that corticosterone can inﬂuence glutamate receptor dynamics through regulation of exocytotic/endocytotic pathways via the Rab GTPases (Liu et al., 2010). Support for the view that chronic GC administration is associated with reduced BDNF signaling comes from evidence that chronic corticosterone treatment in adult animals results in a signiﬁcant decline in phospho-Trk (pTrk) expression within the hippocampus (Gourley et al., 2008b). Decreased pTrkB is accompanied by a reduction in phosphorylated ERK1/2 (pERK1/2) levels in the DG. Attenuated BDNF signaling emerges only following fairly prolonged corticosterone treatment, and appears to be preceded by a decline in hippocampal TrkB protein levels (Gourley et al., 2008b). However in contrast, GC administration in vitro to cortical neurons and in vivo treatment to postnatal day 18 rats has been reported to increase pTrkB expression within the hippocampus in the absence of any change in BDNF (Jeanneteau et al., 2008). In ex vivo cortical slice preparations, dexamethasone treatment resulted in slow-onset increases in pTrkB, pPLC, pAKT and pERK (Jeanneteau et al., 2008). These results suggest that GCs selectively enhance phosphorylation of the Trk receptors and down-stream signaling proteins through GR-mediated genomic eﬀects. The diﬀering eﬀects noted in pTrk expression following chronic GC treatment could be a consequence of the developmental stage in question. It can be hypothesized that GCs play a protective role against excitotoxic damage at early postnatal stages, as would be suggested by increased GC-evoked pTrkB and evidence of reduced susceptibility to glutamate-induced neurotoxicity (Mattson et al., 1995). In contrast, within the mature brain GCs through reductions in pTrkB signaling may serve to enhance vulnerability to excitotoxic damage (Stein-Behrens et al., 1992; MacPherson et al., 2005). While currently highly speculative, the evidence thus far suggests diﬀering eﬀects of GCs on both pTrkB as well as excitotoxic susceptibility, and the age-dependent

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nature of such diﬀerences requires systematic experimental testing. Further, a recent study suggests that progressive enhancement of corticosterone levels can increase the basal activation of ERK suggesting that variation in corticosterone doses may have diﬀerential consequences (Munhoz et al., 2010). BDNF activates several intracellular cascades via the full-length TrkB receptor including MAPK pathways, PI3 kinase and PLCc (reviewed in Reichardt, 2006). The coupling of TrkB to these signaling pathways (Fig. 1(6)) is mediated via speciﬁc intracellular adaptor proteins including Grb2/Src homology-2 domain-containing phosphatase 2 (Shp2) complex for ERK1/2 activation and growth factor receptor-bound protein 2/son of sevenless (Grb2/SOS) complex recruitment for Ras activation (reviewed in Dance et al., 2008). For MAPK activation, Shp2 forms a signaling complex with TrkB and prolongs MAP kinase signaling by dephosphorylating and thus inactivating the MAP kinase inhibitor sprouty (Hanafusa et al., 2004). In vitro studies (Kumamaru et al., 2011) in cortical neurons have demonstrated that dexamethasone treatment inhibits the MAP kinase pathway by altering the TrkB association with Shp2, thus impairing the robust and prolonged activation of the MAP kinase pathway (Kumamaru et al., 2011). Though GCs do not alter the expression or the phosphorylation status of Shp2, they impair TrkB–Shrp2 association (Kumamaru et al., 2011) thus serving as brakes to terminate or limit the duration of BDNFmediated ERK phosphorylation (Fig. 1(6)). Further, MAP-kinase signaling which is downstream of BDNF could also be inﬂuenced by GCs through a modulation of MAP kinase phosphatase-1 (MKP-1) (Kassel et al., 2001) (Fig. 1(6)). Dexamethasone has been shown to reduce pERK levels by enhancing the transcription of the corticosteroid-inducible gene MKP-1 in a variety of cell types including mast cells (Kassel et al., 2001), smooth muscle (Manetsch et al., 2012), pancreatic islets (Nicoletti-Carvalho et al., 2010) and activated microglia (Zhou et al., 2007; Huo et al., 2011), likely through genomic eﬀects via GR. Further, the proteasomal degradation of MKP-1 is also inhibited by GCs thus further serving to enhance MKP-1 levels and to reduce pERK signaling (Kassel et al., 2001). Future studies are required to address whether GC inﬂuence on MKP-1 and Shrp2 plays a role in the GC modulation of ERK signaling in the hippocampus and other brain regions. It is interesting to note that a recent study demonstrates that corticosterone treatment also increases MKP-1 expression within the frontal cortex and hippocampus (Munhoz et al., 2010). In addition to impacting ERK signaling, GCs have also been shown to perturb speciﬁc downstream targets of BDNF such as the BDNFinduced and ERK-mediated upregulation of the microRNA, miR-132 (Kawashima et al., 2010). Corticosterone treatment of cortical neurons in vitro signiﬁcantly attenuated the upregulation of miR-132 by BDNF, likely through an attenuation of pERK signaling (Kawashima et al., 2010). It is important here to note that acute stressors have been reported to evoke a robust enhancement in pERK1/2 levels both within the

PVN of the hypothalamus (Sasaguri et al., 2005; Osterlund et al., 2011) and in the hippocampus (Yang et al., 2004). This diﬀers from the reported eﬀects of GCs, which appear to terminate or reduce ERK signaling (Gourley et al., 2008b). In fact, the eﬀects of stress on PVN pERK expression were augmented in animals that had been adrenalectomized, but ADX animals showed no baseline change in PVN pERK1/2 expression (Osterlund et al., 2011). In contrast, within the hippocampus the eﬀects of stress on pERK were prevented by GR antagonists (Yang et al., 2004). This suggests that GCs have region-speciﬁc roles in contributing to the eﬀects of stress on pERK signaling, where in the hypothalamus they may serve to attenuate some of the eﬀects of stress on pERK signaling (Osterlund et al., 2011), whereas in the hippocampus they are likely mediators of the induction of pERK by stress. A consensus on the contribution of GCs to the eﬀects of stress on BDNF signaling is yet to emerge, with diﬀering eﬀects reported based on the nature of stressor and the brain region examined. The regulation of PLCc signaling by BDNF is also inﬂuenced by GCs (Fig. 1(6)), since dexamethasone treatment has been reported to reduce the BDNFdependent binding of PLC to TrkB in cultured cortical neurons (Numakawa et al., 2009). Cytosolic GR is reported to directly interact with TrkB, an interaction enhances the TrkB–PLCc signaling pathway (Numakawa et al., 2009). Chronic in vitro dexamethasone or corticosterone treatment by downregulation of GR levels, reduces the interaction of TrkB with GR, and serves to decrease the PLCc stimulation by BDNF (Numakawa et al., 2009) (Fig. 1(6)). The eﬀects of GCs could be replicated through knockdown of GR, and the eﬀects of GCs on reducing PLCc activation could be prevented by GR overexpression suggesting that the eﬀects of GCs on the BDNF–PLC pathway were mediated via the TrkB– GR interaction (Numakawa et al., 2009). It is interesting to note recent reports (Jeanneteau et al., 2008) that suggest a direct eﬀect of GCs on TrkB phosphorylation and activation. GCs may also inﬂuence BDNF signaling via the PI3-Kinase–Akt pathway (Zhang and Daynes, 2007). GCs have been shown to increase the expression of the phosphatidylinositol-3,4,5trisphosphate 5-phosphatase 1 (SHIP1), which is a negative regulator of the PI3 kinase pathway (Zhang and Daynes, 2007). GCs in addition to modulation of signaling through intracellular cascades coupled to the TrkB receptor could also inﬂuence the pathways downstream of the p75NTR such as the JNK signaling cascade, NF-jB activation, ceramide signaling and Rho family GTPases (reviewed in Roux and Barker, 2002; Reichardt, 2006). Corticosterone administration has been shown to increase JNK activation within the frontal cortex and the hippocampus in a dose-dependent fashion (Munhoz et al., 2010), and could thus inﬂuence p75NTR-evoked JNK recruitment. While several studies have examined the eﬀects of corticosterone on JNK signaling and NF-jB activation in diverse cell types (Auphan et al.,

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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1995; Ramdas and Harmon, 1998; Li et al., 2001; Qi et al., 2005), these have not been in the context of addressing whether GCs inﬂuence p75NTR-mediated recruitment of these pathways. Thus, there is a lack of understanding of whether GCs could impinge on the low-aﬃnity neurotrophin receptor-based signaling either via an inﬂuence at the level of the receptor itself, or through eﬀects on downstream cascades. In summary, GC regulation of BDNF signaling could occur at multiple levels, through a modulation of the ligand via regulation of its expression, synthesis and secretion, proteolytic processing, modulation of receptor expression, traﬃcking and coupling to signaling cascades, and through interactions of speciﬁc adaptor proteins with the BDNF signaling pathways (Fig. 1). Emerging evidence suggests that GCs may inﬂuence BDNF signaling at several of these diﬀerent levels. However, while substantial investigation has focused on examining regulation at the level of expression of BDNF, thus far limited studies have addressed whether synthesis, traﬃcking, secretion and proteolytic processing of BDNF are targeted by GCs. Further, investigation of the inﬂuence of GCs on BDNF receptors has been largely restricted to the TrkB pathway with little known about the inﬂuence of GCs on the lowaﬃnity p75NTR receptor. The evidence thus far provides strong impetus for future studies that address the mechanistic underpinnings of how GCs regulate both basal and stimulus-evoked BDNF signaling. In the absence of this detailed examination, conclusions regarding the contribution of GCs to the eﬀects of stress on BDNF signaling are still premature, and the current literature does not provide an emerging consensus on whether the eﬀects of stress on BDNF signaling in the brain are mediated via or independent of GCs.

GLUCOCORTICOIDS AND BDNF CROSSTALK: IMPLICATIONS FOR HIPPOCAMPAL STRUCTURAL AND FUNCTIONAL PLASTICITY GCs and BDNF both mediate a potent inﬂuence on various aspects of hippocampal structural (reviewed in Fuchs et al., 2001; reviewed in Yoshii and Constantine-Paton, 2010) and cellular plasticity (reviewed in Schoenfeld and Gould, 2012; reviewed in Schmidt and Duman, 2007), and hippocampaldependent function (reviewed in Kim and Diamond, 2002; Lu et al., 2008) and behavior (reviewed in Duman and Monteggia, 2006; Joe¨ls, 2008). These eﬀects often tend to be opposing in nature. This has led to the working hypothesis that some of the eﬀects of GCs on the hippocampus may be a consequence of evoking a decline in BDNF expression and BDNF-mediated functional outcomes (reviewed in Smith, 1996; Kunugi et al., 2010). The eﬀects of GCs and BDNF on plasticity and hippocampal function have been extensively reviewed elsewhere (Poo, 2001; Schmidt and Duman, 2007; Joe¨ls, 2008; Yoshii and Constantine-Paton, 2010; Schoenfeld and Gould, 2012), and in this review we focus our attention on those studies that directly examine possible functional interactions between GCs and BDNF in their eﬀects on hippocampal plasticity.

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GC and BDNF interactions in the context of cell survival and structural plasticity BDNF functions as a powerful modulator of structural plasticity in the hippocampus (reviewed in Yoshii and Constantine-Paton, 2010) and mediates protective inﬂuences via enhancing neuronal survival (reviewed in Lipsky and Marini, 2007) in particular under conditions of metabolic (Nitta et al., 1999) and excitotoxic insults (Mattson et al., 1995). Conversely, sustained GC exposure leads to dendritic atrophy in hippocampal subﬁelds (Sousa et al., 2000) and decreases neuronal cell survival (Sapolsky et al., 1990), and is also known to evoke a decline in Bdnf expression in hippocampal and cortical regions (Smith et al., 1995b; Dwivedi et al., 2006). While it is unclear whether the decline in Bdnf expression precedes the adverse consequences of GCs on cell survival and synaptic plasticity, as they have not been addressed in the same study, timelines from distinct studies support this possibility. Thus far few studies have tested whether preventing the GC-mediated decline in BDNF, or exogenous BDNF administration, is capable of attenuating the adverse eﬀects of GCs on neuronal survival in vivo. In vitro studies have addressed this possibility by showing that the corticosterone-induced acceleration of neuronal death resulting from serum deprivation (Nitta et al., 1999) is accompanied by reductions in the levels of Bdnf mRNA and protein in cultured hippocampal neurons. Further, exogenously added BDNF attenuates the corticosterone-induced neuronal death, an eﬀect prevented by a Trk inhibitor (Nitta et al., 1999). These observations support the notion that speciﬁc GC eﬀects on neuronal cell death may involve a role for decreased BDNF signaling. GCs and BDNF exert distinct actions on hippocampal neurogenesis with GCs reducing new neuron formation (Cameron and Gould, 1994; Boku et al., 2009) and BDNF serving to promote neurogenesis (Lee et al., 2002; Scharfman et al., 2005). It is important to note that the eﬀects of GCs largely involve a reduction in progenitor proliferation (Cameron and Gould, 1994; Boku et al., 2009), whereas BDNF appears to inﬂuence multiple progenitor stages altering proliferation (Lee et al., 2002; Scharfman et al., 2005) and also promotes progenitor survival (Sairanen et al., 2005) and neuronal diﬀerentiation (Chan et al., 2008). This raises the possibility that GCs and BDNF may inﬂuence distinct progenitor stages, and any functional interactions between these pathways to modulate new neuron generation have yet to be systematically tested. Insights into crosstalk between GC signaling and BDNF come from in vitro evidence (Kumamaru et al., 2008) demonstrating that the BDNF-mediated enhancement in neurite outgrowth of cortical neurons is blocked on pretreatment with dexamethasone. Strikingly, GCs besides blocking neurite outgrowth also prevent the eﬀects of BDNF on the induction of key synaptic proteins namely synapsin and glutamate receptor subunits (Kumamaru et al., 2008). BDNF is also known to promote the formation of synapses and to potentiate the Ca2+ inﬂux evoked by glutamate in mature cortical neurons, eﬀects that were prevented in

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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the presence of dexamethasone (Kumamaru et al., 2008). These eﬀects of GCs are mediated via an inhibition of BDNF-evoked MAP kinase signaling, and likely involve the GR receptor as they are prevented by GR receptor antagonists (Kumamaru et al., 2008). Crosstalk between GCs and BDNF is also supported by evidence from in vivo studies addressing the regulation of hypothalamic CRH expression (Jeanneteau et al., 2012). While BDNF enhances CRH, GR signaling causes a decline in PVN CRH expression. The BDNFmediated induction of CRH transcription involves a role for TrkB-mediated eﬀects on CREB (Jeanneteau et al., 2012). GR abrogates the function of the CREB co-activator CRTC2 thus preventing the BDNF-mediated increases in CRH expression (Jeanneteau et al., 2012). This is an interesting example of how the GR and BDNF pathways may interact to diﬀerentially modulate target gene expression, and provide impetus for future studies to examine in depth the crosstalk between these pathways, in particular in the context of their modulation of hippocampal plasticity. GC and BDNF interaction in the context of synaptic plasticity and hippocampal-dependent behavior Both GCs and BDNF diﬀerentially modulate cellular excitability and inﬂuence LTP. High levels of GCs predominantly impair LTP production and alter Ca2+ inﬂux (reviewed in Prager and Johnson, 2009). In contrast, BDNF largely serves to promote LTP (reviewed in Minichiello, 2009), and inﬂuences cellular excitability by strengthening postsynaptic glutamatergic currents through enhanced activation of glutamatergic receptors and calcium channels (Kovalchuk et al., 2002; reviewed in Minichiello, 2009), and by enhancing the release probability of presynaptic glutamatergic vesicles (Jovanovic et al., 2000). It has been reported that exposure to dexamethasone suppresses BDNF-induced presynaptic glutamate release in cortical neuronal cultures by attenuating the activation of the PLCc/Ca2+ system by BDNF treatment (Numakawa et al., 2009). The decreased activation of the PLCc system following dexamethasone treatment involves a reduction of GR expression, and an ensuing impairment in TrkB–GR interaction, which modulates the coupling of PLC to TrkB (Numakawa et al., 2009). It can be envisioned that the GC-mediated inhibitory eﬀects on BDNF presynaptic neurotransmitter release could contribute to some of the negative eﬀects of GCs on cellular excitability and synaptic plasticity. BDNF and GCs have also been shown to diﬀerentially inﬂuence the Ca2+-activated potassium channel SK2. BDNF-mediated enhancement of LTP is hypothesized to involve a role for the BDNF-mediated phosphorylation and inhibition of SK2 channel function (Krama´r et al., 2004). GCs have been demonstrated to enhance the mRNA expression of SK2 through transcriptional eﬀects at the SK2 promoter (Kye et al., 2007). While the above studies (Kumamaru et al., 2008; Numakawa et al., 2009; Jeanneteau et al., 2012) point to possible stages in the BDNF signaling cascade for functional crosstalk with GCs and their receptors, further

studies are required to address the extent of contribution of BDNF to the eﬀects of GCs on cellular excitability. Concomittant with the largely opposing eﬀects on cellular excitability, GCs (reviewed in Prager and Johnson, 2009) and BDNF also demonstrate contrasting eﬀects on the induction of LTP (Pavlides et al., 1993; Minichiello et al., 1999). It has been reported that exogenous corticosterone application to hippocampal slices signiﬁcantly attenuates tetanus-induced LTP excitatory postsynaptic potential (EPSP) slope and impairs paired-pulse facilitation in CA1 pyramidal neurons (Zhou et al., 2000). These changes arise associated with a signiﬁcant reduction in Bdnf expression in the CA1 hippocampal subﬁeld (Zhou et al., 2000). Strikingly, BDNF co-applied with corticosterone rescued the GC-mediated deﬁcit in paired-pulse facilitation and normalizes the GC eﬀects on EPSP slope (Zhou et al., 2000). Further, chronic BDNF infusion was also capable of ameliorating the chronic stress-induced impairments in hippocampal LTP and spatial learning and memory (Radecki et al., 2005). These results suggest that speciﬁc eﬀects of GCs and stress on hippocampal synaptic plasticity are likely to involve an important role for BDNF. While GCs and BDNF exert largely opposing eﬀects on LTP, their inﬂuence on learning and memory is not as distinct. While BDNF largely promotes learning and improves hippocampal-dependent cognitive function (reviewed in Tyler et al., 2002), the inﬂuence of GCs on learning and memory is highly dependent on dose, timing and context of GC administration with respect to the cognitive task (Korz and Frey, 2003; reviewed in Kim and Diamond, 2002). GC administration has been shown to both evoke impairments (reviewed in Sandi and Pinelo-Nava, 2007) and improve performance (Sandi et al., 1997) on hippocampal-dependent learning and memory paradigms. Animal models of depression and anxiety are associated with disrupted HPA axis function (Henn and Vollmayr, 2005; Touma et al., 2008; Bowens et al., 2011). Chronic GC administration itself serves as an animal model for depression (Gourley et al., 2008a,b), mimicking speciﬁc components of the endophenotypes observed in clinical depression. While animals exposed to elevated GC levels exhibit increased anxiety, anhedonia and depressive behaviors (Gourley et al., 2008a,b), BDNF administration evokes largely opposing eﬀects with a decrease in anxiety and depressive behaviors (Shirayama et al., 2002). The mood-related behavioral eﬀects of GCs and BDNF in animal models are predominantly contrasting in nature. Animal models of depression generated by elevating GC levels also show a robust decline in hippocampal BDNF that accompanies the behavioral changes in these models (Gourley et al., 2008a,b; Diniz et al., 2011). Strikingly, hippocampal BDNF infusion in animals receiving chronic corticosterone was capable of rescuing the depressivelike behavior evoked by GC exposure on the forced swim test (Gourley et al., 2008a). Future experiments are required to test whether the mood-modulating actions of GCs involve a role for abrogating or preventing the anti-depressant like eﬀects of BDNF.

Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

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CONCLUSIONS In summary, the regulation of BDNF by GCs is likely to occur at multiple levels in the BDNF signaling pathway, with most evidence thus far for eﬀects of GCs on Bdnf mRNA expression. Several studies also suggest that GCs may alter BDNF signaling by modulating downstream signal transduction cascades for the ERK, PLC and PI3–Akt pathways. However, few studies have thus far examined whether GCs inﬂuence BDNF synthesis, stability, traﬃcking, processing or release, or addressed eﬀects at the levels of the TrkB receptor isoforms and p75NTR. Given the current working hypothesis that some of the negative eﬀects of GCs on structural and synaptic plasticity arise by evoking a decline in BDNF signaling, it is essential to gain an indepth mechanistic insight of how GCs impinge on the regulation of BDNF at multiple levels. Further, it is important to understand the reciprocal crosstalk between GCs and their receptors, and BDNF signaling pathways, to place in context how these pathways may interact under physiological conditions including stress, and contribute to the genesis of pathophysiological states.

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(Accepted 30 August 2012) (Available online xxxx) Please cite this article in press as: Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity. Neuroscience (2012), http://dx.doi.org/10.1016/j.neuroscience.2012.08.065

Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity

Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity

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