Elsevier

Neuropharmacology

Volume 102, March 2016, Pages 72-79
Neuropharmacology

Review article
BDNF – a key transducer of antidepressant effects

https://doi.org/10.1016/j.neuropharm.2015.10.034Get rights and content

Highlights

  • Antidepressant drugs, e.g. SSRIs, increase BDNF in the hippocampus and PFC.

  • Ketamine rapidly increases BDNF protein levels in the hippocampus.

  • Ketamine elicits hippocampal potentiation dependent on BDNF expression.

  • BDNF is required for the antidepressant effects of traditional antidepressant drugs and ketamine.

  • BDNF may serve as a key transducer of antidepressant effects.

Abstract

How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.

Introduction

Brain-derived neurotrophic factor (BDNF) is a well-studied growth factor that serves many critical functions within the central nervous system (CNS). BDNF has a role in processes such as neuronal maturation, synapse formation and synaptic plasticity among others in the brain (see e.g. Park and Poo, 2013). BDNF has also been implicated in a number of psychiatric disorders, including schizophrenia, intellectual disability and autism, and the development of mood disorders such as depression and its treatment (Autry and Monteggia, 2012).

BDNF is a member of the neurotrophin family that includes nerve growth factor (NGF), neurotrophin-3 (NT3), and neutorophin-4 (NT4). BDNF is widely expressed in the CNS and can exert profound effects on development, morphology, and synaptic plasticity and function in the brain. The BDNF gene has nine promoters that drive expression of distinct Bdnf transcripts that each encode the same BDNF protein (Aid et al., 2007, Pruunsild et al., 2007). These individual Bdnf transcripts may contribute to regional and temporal specific effects of BDNF and is an active area of investigation. The transcription of BDNF mRNA can be regulated by neuronal activity via Ca2+ influx, through Ca2+ permeable glutamate receptors (mainly N-Methyl-d-aspartate [NMDA] receptors) and voltage gated Ca2+ channels (Ghosh et al., 1994, Zafra et al., 1991). Previous work has shown that Ca2+ initiates the binding of transcription factors such as cyclic AMP response element binding protein (CREB) and Ca2+ response factor (CaRF) to the BDNF promoters (Tao et al., 1998, Tao et al., 2002). Activity-dependent BDNF transcription can also be regulated by epigenetic changes of the chromatin structure, adding yet another level of regulation (Kumar et al., 2005a, Zhou et al., 2006).

BDNF is synthesized in cell bodies of neurons and glia and transported to terminals where it is released (Lessmann and Brigadski, 2009). However, BDNF can also be directed to dendrites, where activity dependent local translation of BDNF takes place (Lau et al., 2010). BDNF is first synthesized into pre-pro-BDNF, which is cleaved to mature BDNF, however, the exact location of this conversion (inside the cell or after secretion extracellularly) remains unclear (see e.g. Leal et al., 2014). BDNF secretion is activity dependent, and BDNF has been shown to be secreted both by presynaptic and postsynaptic terminals, although at different stimulation intensities (Matsuda et al., 2009). The cell biology of BDNF processing and trafficking is complex and remains an open question therefore we refer the readers to a recent review on this topic (please see e.g. Karpova, 2014).

BDNF binds with high affinity to the tropomycin receptor kinase B (TrkB) receptor (Soppet et al., 1991). BDNF, like other members of the neurotrophin family, can also bind to the p75 neurotrophin receptor although with lower affinity (Meeker and Williams, 2015). Many studies have established a critical role for BDNF-TrkB in synaptic plasticity mechanisms. TrkB receptors are expressed both pre- and postsynaptically and BDNF has been shown to regulate neurotransmitter release as well as postsynaptic responses (Madara and Levine, 2008). BDNF binding to TrkB can regulate at least three intracellular signaling pathways (Park and Poo, 2013). One pathway involves phospholipase C-γ (PLC- γ) leading to protein kinase C (PKC) activation. A second involves mitogen-activated protein (MAP) kinase, which can activate Ras leading to downstream effects. A third signaling pathway involves phosphatidylinositol-3′OH-kinase (PI3K) that can activate the AKT-mTOR pathway.

As mentioned previously, BDNF-TrkB signaling can modulate neurotransmission and enhance synaptic efficacy both via presynaptic and postsynaptic mechanisms in a variety of ways. BDNF facilitates high frequency activity induced long-term potentiation (LTP) in the Schaffer collaterals of the hippocampus in young animals by enhancing presynaptic neurotransmitter release (Figurov et al., 1996). BDNF infusion into the hippocampus may also induce LTP in vivo (Ying et al., 2002), confirming the physiological relevance of this finding. Presynaptic release of BDNF has been shown to be critical for LTP-induction in the hippocampus Schaffer collaterals (Zakharenko et al., 2003). In the dentate gyrus (DG) subregion of the hippocampus, BDNF can facilitate LTP though postsynaptic mechanisms (Kovalchuk et al., 2002). BDNF may also increase the postsynaptic response by increasing conductance of NMDA receptors (Levine et al., 1995, Levine et al., 1998). BDNF has been shown to increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses by enhancing AMPA receptor translation and cell surface expression (Caldeira et al., 2007, Fortin et al., 2012). In addition, BDNF can facilitate excitatory transmission indirectly by attenuating inhibitory neurotransmission by, for example, reducing the surface expression of GABAA receptors (Jovanovic et al., 2004). BDNF via TrkB signaling has been found to increase spine density in the hippocampus via several signaling pathways (Alonso et al., 2004, Amaral and Pozzo-Miller, 2007, Kumar et al., 2005b). Moreover, LTP-induced enlargement of hippocampal dendritic spine volume is dependent on BDNF signaling and local protein translation (Tanaka et al., 2008). Recent studies have also identified a key role for BDNF in synaptic potentiation seen after sustained blockade of NMDA receptor activity, where BDNF action appears to upregulate postsynaptic AMPA receptors (Autry et al., 2011, Nosyreva et al., 2013).

Given the crucial importance of BDNF in the developing and mature CNS, it is not surprising that disturbances in BDNF expression can affect brain function. Single nucleotide polymorphisms (SNPs), have been identified in the BDNF gene, which has provided an opportunity to study individuals carrying these SNPs (See e.g. Egan et al., 2003, Hing et al., 2012). The best characterized SNP in the BDNF gene is located in the pro-BDNF region, changing codon 66 from a valine (val) to methionine (met; i.e. val66met). Individuals with the val66met SNP have reduced episodic memory and aberrant hippocampal function that is believed to be due to disturbed intracellular trafficking and activity dependent secretion of BDNF (Egan et al., 2003). The val66met SNP has also been suggested to play a role in the vulnerability to several psychiatric disorders and traits; including mood disorders and impaired cognition (Notaras et al., 2015). Interestingly, symptoms analogous to their human counterparts have been found in genetically modified mice carrying the human BDNF val66met alleles. These mice display working memory deficits as well as an anxious and depressive-like phenotype in response to stress (Yu et al., 2012). In addition, these mutant mice have reduced synaptic plasticity and synaptic transmission in both hippocampus and the medial prefrontal cortex (mPFC; Ninan et al., 2010, Pattwell et al., 2012). Another SNP, BE5.2, located in a cis-regulatory region that controls the activity of a BDNF promoter in the hippocampus, cortex and the amygdala, has been identified (Hing et al., 2012). This SNP reduces evoked release of BDNF in the hippocampus and cortex and is also associated with mood disorders. In contrast, in the amygdala, BE5.2 increases BDNF release, which may provide a mechanistic explanation for this SNP's linkage to the development of anxiety disorders (Hing et al., 2012).

Section snippets

BDNF and the response to conventional antidepressants

Clinically used antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs), mediate their antidepressant effect by modulating the extracellular levels of monoamines mainly serotonin or norepinephrine. It is generally thought that these drugs enhance the extracellular levels of monoamines rather quickly, within hours; however, the antidepressant response is delayed and typically requires weeks of treatment before a sufficient antidepressant

BDNF is required for the rapid antidepressant effects of ketamine

The discovery that an acute low dose of ketamine, a noncompetitive NMDA receptor antagonist, can trigger rapid antidepressant effects in patients with depression, including treatment-resistant depression, has generated a great deal of interest in unraveling the underlying biological mechanisms mediating the fast acting response (Berman et al., 2000, DiazGranados et al., 2010a, DiazGranados et al., 2010b, Price et al., 2009, Zarate et al., 2006a). Acute intravenous administration of low dose

Discussion and future perspectives

Current evidence strongly implicates BDNF-TrkB signaling in the response to clinically used antidepressant drugs including ketamine. Indeed, as stated above, conventional antidepressants as well as ketamine require BDNF to mediate their antidepressant effects. Thus, it is possible that while there may be differences in how conventional antidepressants and ketamine trigger an antidepressant response, BDNF may be the point of convergence for the antidepressant effect of these drugs.

While BDNF has

Acknowledgments

This work was supported by National Institute of Health grant MH070727, as well as awards from the Brain & Behavior Research Foundation, the International Mental Health Research Organization, and the Jordan Elizabeth Harris Foundation (L.M.M.). CB was supported by a post doctoral fellowship from the Elisabeth and Alfred Ahlqvist foundation within the Swedish Pharmaceutical Society. The authors would like to thank members of the Monteggia laboratory for helpful discussions and comments on the

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