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.Depression and anxiety disorders have genetic predispositions, yet the particular genes that contribute to this pathology are not known. One candidate gene is BDNF, because of its established roles in neuronal survival, differentiation, and synaptic plasticity. The recent discovery of a single-nucleotide polymorphism (SNP) in the bdnf gene (Val66Met), found only in humans, leading to a Met substitution for Val at codon 66 in the prodomain, has provided a valuable tool to assess potential contributions of BDNF to affective disorders. This polymorphism is common in human populations with an allele frequency of 20 to 30% in Caucasian populations (1). This alteration in a neurotrophin gene correlates with reproducible alterations in human carriers. Humans heterozygous for the Met allele have smaller hippocampal volumes (2-4) and perform poorly on hippocampal-dependent memory tasks (5,6). However, in genetic association studies for depression and anxiety disorders, there is little consensus as to whether this allele confers susceptibility.The mechanisms that contribute to altered BDNF Met function have been studied in neuronal culture systems. The distribution of BDNF Met to neuronal dendrites and its activity-dependent secretion are decreased (6-8). These trafficking abnormalities are likely to reflect impaired binding of BDNF Met to a sorting protein, sortilin, which interacts with BDNF in the prodomain †To whom correspondence should be addressed.

Brain-derived neurotrophic factor (BDNF), after activity-dependent secretion from neurons, modulates critical nervous system functions. Recently, a variant in the human bdnf gene, resulting in a valine to methionine substitution in the prodomain, has been shown to lead to defective regulated secretion from neurons and memory impairment. Here, we report a novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated secretory pathway. Sortilin interacts specifically with BDNF in a region encompassing the methionine substitution and colocalizes with BDNF in secretory granules in neurons. A truncated form of sortilin causes BDNF missorting to the constitutive secretory pathway without affecting neurotrophin-4 (NT-4) secretion. In addition, sortilin small interfering RNA introduced into primary neurons also led to BDNF missorting from the regulated to the constitutive secretory pathway. Together, these data suggest a mechanism to understand the defect associated with variant BDNF and provide a framework, based on divergent presynaptic regulation of sorting to secretory pathways, to explain how two ligands for tropomyosin-related kinase B, BDNF and NT-4, can mediate diverse biological responses.