Brain-Derived Neurotrophic Factor for Depression Therapeutics

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. therapeutics (e.g., antidepressants and brain stimulations, 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] ( [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 intriguing hypothesis 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-dependent BDNF Introduction 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 onethird 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.