Progress in the “brain-derived neurotrophic factor hypothesis of depression”

The traditional ＂brain-derived neurotrophic factor （BDNF） hypothesis of depression＂ proposes that impairment of the BDNF signaling pathway in the hippocampus and prefrontal cortex participates in the pathophysiology of depression, and antidepressants act by recovering/enhancing BDNF signal transduction. Recent studies have suggested that BDNF signaling pathways exert more diverse and complex effects on depression onset and antidepressant therapy than originally thought, which include： （1） inhibition of the BDNF-TrkB signaling pathway in the hippocampus and/or prefrontal cortex does not induce the depression-like behavioral phenotype, but significantly diminishes therapeutic effects, which suggests that the BDNF-TrkB signaling pathway lacks direct or key effects on occurrence of emotional disorders, whereas an intact and normal BDNF-TrkB signaling pathway is necessary for antidepressant therapy. （2） The BDNF-TrkB signaling pathway exhibits opposite regulatory effects on depressive behavior in the hippocampus-prefrontal cortex network and mesolimbic system, which suggests that BDNF regulates emotion by affecting the emotion-related neural network, but not a single brain region. （3） The BDNF-TrkB and proBDNF-p75Nm signaling pathways in the brain, respectively, enhance and suppress hippocampal neural plasticity, which demonstrated that different BDNF signaling pathways interact and restrict each other in the regulation of neural plasticity and emotional behaviors. （4） BDNF gene polymorphism might be associated with susceptibility to depression. These new findings extend our understanding of neuronal pathways and mechanisms of action of BDNF signaling and contribute to improved views to traditional ＂neurotrophic factor hypothesis of depression＂.