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) is best characterized for critical roles in neuronal survival, differentiation, and synaptic modulation mediated by the TrkB receptor tyrosine kinase. Developmentally regulated death signaling by BDNF has also been demonstrated via activation of p75 NTR . Because recent studies suggest that proNGF, the precursor form of NGF, is more active than mature NGF in inducing apoptosis after binding to p75 NTR and a coreceptor, sortilin, we asked whether the precursor of BDNF (proBDNF) is also a proapoptotic ligand in the nervous system. proBDNF is secreted by cultured neurons, and recombinant proBDNF binds to sortilin. In sympathetic neurons coexpressing sortilin and p75 NTR , we found that proBDNF is an apoptotic ligand that induces death at subnanomolar concentrations. In contrast, mature BDNF, but not proBDNF, is effective in inducing TrkB phosphorylation. proBDNF effects are dependent on cellular coexpression of both p75 NTR and sortilin, because neurons deficient in p75 NTR are resistant to proBDNF-induced apoptosis, and competitive antagonists of sortilin block sympathetic neuron death. Moreover, addition of preformed complexes of soluble sortilin and proBDNF failed to induce apoptosis of cells coexpressing both sortilin and p75 NTR , suggesting that interaction of proBDNF with both receptors on the cell surface is required to initiate cell death. Together with our past findings, these data suggest that the neurotrophin family is capable of modulating diverse biological processes via differential processing of the proneurotrophins.
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