Neuroscience 239 (2013) 196–213

REVIEW

GLUCOCORTICOID REGULATION OF BRAIN-DERIVEDNEUROTROPHIC FACTOR: RELEVANCE TO HIPPOCAMPALSTRUCTURAL AND FUNCTIONAL PLASTICITY

D. SURI AND V. A. VAIDYA *

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 conse-

quences on the brain, in particular within the hippocampus.

Chronic glucocorticoid exposure evokes neuronal cell dam-

age and dendritic atrophy, reduces hippocampal neurogen-

esis and impairs synaptic plasticity. Glucocorticoids also

alter expression and signaling of the neurotrophin, brain-

derived 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 glucocor-

ticoids 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 glu-

cocorticoids 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 receptor-

mediated signaling. Further, we delineate potential lines of

future investigation to address hitherto unexplored aspects

of the influence of glucocorticoids on BDNF. Finally, we dis-

cuss 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 hippo-

campus. Understanding the mechanistic crosstalk between

glucocorticoids and BDNF holds promise for the identifica-

0306-4522/13 $36.00 � 2012 IBRO. Published by Elsevier Ltd. All rights reservehttp://dx.doi.org/10.1016/j.neuroscience.2012.08.065

*Corresponding author. Tel: +91-22-22782608; fax: +91-22-22804610.

E-mail address: vvaidya@tifr.res.in (V. A. Vaidya).Abbreviations: ADX, adrenalectomy; AP-1, activator protein-1; BDNF,brain-derived neurotrophic factor; CREB, cyclic AMP responseelement-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-terminalkinase; LTP, long-term potentiation; MAPK, mitogen-activated proteinkinase; MKP-1, MAP kinase phosphatase-1; MMPs, matrixmetalloproteinases; MR, mineralocorticoid receptor; NF-jB, nuclearfactor-jB; p75NTR, p75 neurotrophin receptor; PC, prohormoneconvertases; PI3-Akt, phosphatidylinositol-3-kinase-Akt; PLCc,phospholipase C-c; PVN, paraventricular nucleus; tPA, tissueplasminogen activator; TrkB, tropomyosin-related kinase B.

196

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

hormone actions in the CNS: the role of BDNF.

� 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Key words: hormone, glucocorticoid receptor, neurotrophin,

tropomyosin-related kinase B, mitogen-activated protein

kinase, stress.

Contents

Introduction 196

Glucocorticoids 197

BDNF 198

Regulation of BDNF 199

Glucocorticoid regulation of BDNF expression 201

Influence of glucocorticoids on Bdnf transcription 201

Influence of glucocorticoids on exon-specific Bdnf transcript

variants 202

Influence of glucocorticoids on Bdnf mRNA stability 202

Influence of glucocorticoids on BDNF translation, processing,

trafficking and secretion 202

Stress regulation of BDNF 202

Glucocorticoid receptors and BDNF 203

Glucocorticoid regulation of BDNF signaling 204

Glucocorticoids and BDNF crosstalk: implications for hippo-

campal structural and functional plasticity 206

GC and BDNF interactions in the context of cell survival and

structural plasticity 206

GC and BDNF interaction in the context of synaptic plasticity

and hippocampal-dependent behavior 207

Conclusions 208

References 208

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 Joels, 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

d.

D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213 197

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 psychologi-

cal 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 adreno-

corticotrophic 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 non-

genomic 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

198 D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213

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 self-

sustaining cycle of HPA axis dysregulation. Several

previous reviews (Joels, 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 Bdnftranscript 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 neurotrans-

mission 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

D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213 199

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 sortilin-

dependent modulation of BDNF trafficking. The complex

gene structure of Bdnf allows exon-specific Bdnfpromoters 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 methyl-

CpG-binding protein 2 (MeCP2) (Chen et al., 2003), in

the regulation of the expression of specific Bdnftranscript 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 30UTR 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 RNA-

binding 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 Bdnfexpression, 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 30UTRs differentially influence the translatability

and stability of Bdnf mRNA (Fukuchi and Tsuda, 2010).

Short 30UTR Bdnf transcripts are linked to basal BDNF

synthesis and the long 30UTR 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; Kruttgen et al., 1998; reviewed

in Thomas and Davies, 2005). The trafficking of pro-

BDNF 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

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.

200 D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213

D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213 201

proteins (Fig. 1). TrkB exists as both the catalytic full-

length 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 inositol-

1,4,5-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 BDNFEXPRESSION

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 BdnfmRNA 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 Bdnfexpression, 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 situhybridization 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

202 D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213

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 Bdnftranscript 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 Bdnfexpression 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 CREB-

mediated 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

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 30UTR, is altered by GC exposure. It is of

interest to note that GCs have been shown to influence

the stability of specific mRNAs including pre-

proglucagon (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 demonstrat-

ing that BDNF polymorphisms (BDNFVal66Met) alter the

regulated, in particular activity-dependent, secretion of

BDNF (Egan et al., 2003) through perturbation of pro-

BDNF–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

D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213 203

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 (Marmigere et al., 2003; Molteni et al., 2009;

Neeley et al., 2011). Overall, the evidence suggests that

the effects of stress and GC exposure on Bdnfexpression 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 Bdnfexpression 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 stress-

mediated 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 contribu-

tion 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-Herbruggen et al., 2007; Molteni et al., 2010),

and the hypothalamus (Schulte-Herbruggen 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

204 D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213

hippocampal (Ridder et al., 2005) and amygdaloid

(Schulte-Herbruggen 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, stress-

responsivity and behavior (reviewed in Kolber et al.,

2008). Future studies with conditional GR and MR

mutants that restrict the genetic perturbation spatio-

temporally would provide important insights into the

manner in which GC receptors modulate BDNF

expression and signaling.

GLUCOCORTICOID REGULATION OF BDNFSIGNALING

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 trkBtranscriptional 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.FLexpression (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,

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

D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213 205

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 BDNF-

mediated 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 BDNF-

induced and ERK-mediated upregulation of the

microRNA, miR-132 (Kawashima et al., 2010).

Corticosterone treatment of cortical neurons in vitrosignificantly 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 BDNF-

dependent 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 vitrodexamethasone or corticosterone treatment by

downregulation of GR levels, reduces the interaction of

TrkB with GR, and serves to decrease the PLCcstimulation 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-3,4,5-

trisphosphate 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-jBactivation, 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.,

206 D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213

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 low-

affinity 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 hippocampal-

dependent function (reviewed in Kim and Diamond,

2002; Lu et al., 2008) and behavior (reviewed in Duman

and Monteggia, 2006; Joels, 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; Joels, 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.

GC and BDNF interactions in the context of cellsurvival 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 Bdnfexpression 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

D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213 207

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 BDNF-

mediated 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 synapticplasticity 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

(Kramar 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 depressive-

like 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.

208 D. Suri, V. A. Vaidya /Neuroscience 239 (2013) 196–213

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 in-

depth 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 9 September 2012)