Brain-Derived Neurotrophic Factor for Depression Therapeutics

Review Article

Austin J Pharmacol Ther. 2014;2(1): 1006.

Brain-Derived Neurotrophic Factor for Depression Therapeutics.

Kazuko Sakata *

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA

*Corresponding author: : Kazuko Sakata, Department of Pharmacology/Psychiatry, College of Medicine,University of Tennessee Health Science Center, 874 Union Ave, Room 430, Memphis, TN 38163

Received: January 01, 2014; Accepted: January 22, 2014; Published: January 27, 2014;


Increasing evidence over the last two decades has indicated that the pathophysiology of major depressive disorder (MDD) and the action of antidepressants both involve brain-derived neurotrophic factor (BDNF), a major neuronal growth factor in the brain. MDD is a complex disorder that results from genetic and environmental influences, singly or in combination. This article reviews the current knowledge of BDNF and depression therapeutics, focusing especially on the gene regulation of BDNF and other BDNF–related mechanisms for recent depression therapeutics, including glutamatergic antidepressants and brain stimulation. It is still unclear why some people are more susceptible to MDD and why many show individual differences in their treatment responses.This article also briefly reviews more recent findings on the epigenetic and genetic status of the BDNF gene in brain and blood, which may explain MDD susceptibility and predict response to depression treatment.


Major depressive disorder (MDD) is the leading cause of disability in developed countries (˜350 million people are affected worldwide), with devastating symptoms including depressed mood, loss of interest or pleasure, executive dysfunctions, psychomotor retardation, suicide ideation, and eating and sleep disturbances [1]. However, the current treatment outcome is suboptimal—only one–third of patients show remission after a first–line treatment and only about a half of patients show complete remission following multiple treatments that take several months to years [2]. A more efficacious treatment and preventions are needed to combat MDD and to increase quality of life and reduce the disease burden. It is therefore imperative to understand the mechanisms of this disorder and its recovery.

BDNF and depression

A large body of evidence over the past decade has suggested that the pathophysiology of MDD and its recovery involve gene regulation of brain–derived neurotrophic factor (BDNF) [3–6]. BDNF is a major neuronal growth factor in the brain, which regulates neurogenesis, neuronal maturation and survival, and synaptic plasticity. Low levels of BDNF have been observed in the brain of suicide subjects and depressed patients [7–10], particularly in the regions (i.e., hippocampus, prefrontal cortex, and amygdala) that show atrophy in depressed patients and stressed animals [11–13]. Reduced BDNF levels have been also observed in blood of depressed patients, and these low levels can be reversed following depression treatment [14]. Causal relations between stress and BDNF have been clarified by using rodents; physical stress (acute and chronic immobilization) and corticosterone (a hormone induced by stress) have been shown to decrease BDNF levels in the hippocampus [15]. Negative environmental effects like psychological stress (re–exposure to cue associated with foot shocks [16] and chronic social defeat [17]) and chronic alcohol intake [18] also decrease BDNF levels in the hippocampus. On the other hand, different types of depressiontherapeutics (e.g., antidepressants and brain stimulations, see 3 and 4 below) increase BDNF levels and can reverse the stress–induced BDNF reduction [19]. Direct antidepressant effects of BDNF have been also reported; infusion of BDNF into the hippocampus produced sustained antidepressant–like effects in rodents [20–23]. These findings give hope that increasing the levels of BDNF in the related brain regions and targeting the involved pathways may become a new strategy for the prevention and treatment of MDD.

Gene regulation of BDNF

The expression of BDNF is tightly regulated by at least 9 promoters in both humans [24,25] and rodents [26,27]. Each promoter regulates BDNF expression differently in a region/cell–specific manner and has distinct function responding to stress, neuronal activity, and MDD treatments (see [6] for review). Stress reduces the activity of BDNF promoters IV and VI through epigenetic regulation processes that involve increases in histone H3 lysine 27 (H3K27) trimethylation [17,28] (see [29] for detailed epigenetic mechanisms of the BDNF gene). Recent studies have shown that the post–mortem brain of suicidal human subjects also display increased methylation at BDNF promoter/exon IV; this reduces transcription of the Bdnf gene [30]. Further, early–life maltreatment of infants has been reported to increase methylation of the promoter IV–controlled Bdnf DNA (exons IV and IX) and leads to persistent reduction in BDNF expression in the prefrontal cortex in adulthood [31]. Our group recently showed that a lack of promoter IV–driven BDNF [32] leads to depressionlike behavior in mice [33]. Promoter IV is the best–known activitydependent promoter among the known promoters; it responds to neuronal activity to increase BDNF levels [34–36], particularly in the cortex and hippocampus [37,38]. These findings suggest an intriguinghypothesis for critical roles of activity–dependent expression of BDNF in sustaining neuronal activity by a positive feedback mechanism [6]; namely, increased neuronal activity induces activity–dependent BDNF expression, which then induces neuronal activity to maintain active brain functions. Any disruption in the activity–dependentBDNF expression would therefore lead to a decrease in neuronal activity and function, which could in turn lead to depression [Figure 1].

It should be noted that BDNF increases activity/functions of both excitatory and inhibitory neurons. In particular, activity–driven BDNF expression is critical for increasing maturation and functions of the GABAergic inhibitory neurons [32,39–42]. Thus, the activated excitatory neurons likely receive tight inhibition by thenearby GABAergic neurons via the activity–driven BDNF expression. This enhancement of neuronal excitation and inhibition may increase synchronous neuronal activity in a neuronal circuit to control timingdependent signal processing [32]. The enhanced timing–dependentexcitation and inhibition may be critical for flexible learning (e.g., extinction of bad memories and fear) and recovery from MDD [43]. The neural functions of BDNF in the neuronal network including all kinds of neurons remain to be elucidated in the future.

Citation: Sakata K. Brain-Derived Neurotrophic Factor for Depression Therapeutics. Austin J Pharmacol Ther. 2014;2(1): 1006. ISSN: 2373-6208.