Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior

TLDR

A common SNP in BDNF (Val66Met) is linked to brain anatomy and memory changes, but its clinical relevance remains unclear. We generated a BDNF Met/Met mouse that reproduces the phenotypic hallmarks seen in humans carrying the variant allele. BDNF Met/Met mice show normal BDNF expression but defective neuronal secretion, resulting in heightened anxiety-like behaviors that fluoxetine does not rescue, indicating the variant may contribute to anxiety and depressive disorder risk.

Abstract

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.