A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, Val66Met, is associated with altered brain anatomy and memory. This study investigates the role of the Val66Met polymorphism in anxiety-related behaviors. Researchers generated a variant BDNF mouse (BDNF Met/Met) that reproduces human phenotypic hallmarks. BDNF Met was expressed at normal levels in the brain, but its secretion from neurons was defective. BDNF Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant fluoxetine. These findings suggest that the Val66Met polymorphism may play a key role in genetic predispositions to anxiety and depressive disorders. Depression and anxiety disorders have genetic predispositions, but the specific genes involved are not well understood. BDNF is a candidate gene due to its roles in neuronal survival, differentiation, and synaptic plasticity. The Val66Met polymorphism in the BDNF gene has been associated with altered hippocampal volume and hippocampus-dependent memory in humans. However, there is little consensus on whether this allele confers susceptibility to these disorders. The study found that BDNF Met/Met mice had decreased hippocampal volume and impaired hippocampus-dependent memory, similar to human carriers. These mice also exhibited increased anxiety-related behaviors in various tests, including the open-field and elevated plus maze tests. The decreased response to fluoxetine in BDNF Met/Met mice suggests that this polymorphism may affect the efficacy of antidepressants. The study also found that BDNF Met/Met mice had altered neuronal morphology and dendritic complexity, contributing to their behavioral deficits. These findings indicate that the Val66Met polymorphism may influence anxiety-related behaviors through altered BDNF function. The study highlights the importance of genetic factors in anxiety disorders and suggests that BDNF may be a target for therapeutic interventions. The BDNF Met/Met mouse model provides a valuable tool for studying the genetic basis of anxiety and developing new treatments.A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, Val66Met, is associated with altered brain anatomy and memory. This study investigates the role of the Val66Met polymorphism in anxiety-related behaviors. Researchers generated a variant BDNF mouse (BDNF Met/Met) that reproduces human phenotypic hallmarks. BDNF Met was expressed at normal levels in the brain, but its secretion from neurons was defective. BDNF Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant fluoxetine. These findings suggest that the Val66Met polymorphism may play a key role in genetic predispositions to anxiety and depressive disorders. Depression and anxiety disorders have genetic predispositions, but the specific genes involved are not well understood. BDNF is a candidate gene due to its roles in neuronal survival, differentiation, and synaptic plasticity. The Val66Met polymorphism in the BDNF gene has been associated with altered hippocampal volume and hippocampus-dependent memory in humans. However, there is little consensus on whether this allele confers susceptibility to these disorders. The study found that BDNF Met/Met mice had decreased hippocampal volume and impaired hippocampus-dependent memory, similar to human carriers. These mice also exhibited increased anxiety-related behaviors in various tests, including the open-field and elevated plus maze tests. The decreased response to fluoxetine in BDNF Met/Met mice suggests that this polymorphism may affect the efficacy of antidepressants. The study also found that BDNF Met/Met mice had altered neuronal morphology and dendritic complexity, contributing to their behavioral deficits. These findings indicate that the Val66Met polymorphism may influence anxiety-related behaviors through altered BDNF function. The study highlights the importance of genetic factors in anxiety disorders and suggests that BDNF may be a target for therapeutic interventions. The BDNF Met/Met mouse model provides a valuable tool for studying the genetic basis of anxiety and developing new treatments.