A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF ^Met/Met ) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF _Met was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF ^Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.

Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found humanBDNFVal66Met (BDNF_Met) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between theBDNF_Metpolymorphism and stress are unclear. We found that heterozygousBDNF^+/Metmice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover,BDNF^+/Metmice exhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors inBDNF^+/Metmice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human geneticBDNF_Metpolymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects onBDNF^+/Metmice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF.

Brain-derived neurotrophic factor (BDNF) plays important roles in activity-dependent plasticity processes, such as long-term potentiation, learning, and memory. The recently reported human BDNF Val66Met (BDNF_Met) polymorphism has been shown to lead to altered hippocampal volume and impaired hippocampal-dependent memory and is associated with a variety of neuropsychiatric disorders. There are few studies, however, that investigate the effect of the BDNF_Metpolymorphism on hippocampal-independent memory processes. A conditioned taste aversion (CTA) task was used for studying the mechanisms of long-term, hippocampal-independent, nondeclarative memory in the mammalian brain. Using the CTA paradigm, we found a novel impairment in extinction learning, but not acquisition or retention, of aversive memories resulting from the variant BDNF_Met. BDNF_Metmice were slower to extinguish an aversive CTA memory compared with wild-type counterparts. Moreover, the BDNF_Metwas associated with smaller volume and decreased neuronal dendritic complexity in the ventromedial prefrontal cortex (vmPFC), which plays a significant role in extinction of CTA. Finally, this delay in extinction learning could be rescued pharmacologically with a cognitive enhancer,d-cycloserine (DCS). To our knowledge, this is the first evidence that the BDNF_Metpolymorphism contributes to abnormalities in memory extinction. This abnormality in extinction learning may be explained by alterations in neuronal morphology, as well as decreased neural activity in the vmPFC. Importantly, DCS was effective in rescuing this delay in extinction, suggesting that when coupled with behavior therapy, DCS may be an effective treatment option for anxiety disorders in humans with this genetic variant BDNF.