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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: [email protected] (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)