Brain derived neurotrophic factor (BDNF) regulates neuronal survival, differentiation, and synaptic plasticity. There has been speculation that its genetic alteration might contribute to affective and anxiety disorders. A report by Chen et al. in the Oct. 6 issue of Science now shows that a genetic mutation in humans that changes a single amino acid (valine to methionine) in BDNT can be reproduced in transgenic mice. Transgenic mice heterozygous for the Met allele, like humans, have smaller hippocampal volumes and perform poorly on hippocampal-dependent memory tasks.
Subsequent analyses of these mice elucidated a phenotype that had not been established in human carriers: increased anxiety. When placed in conflict settings, transgenic mice homozygous for the Met allele displayed increased anxiety-related behaviors in three separate tests, suggesting a genetic link between BDNF and anxiety. Some genetic association studies in humans have found that the Met allele has been associated with increased trait anxiety, but other studies have not replicated these findings. The anxiety-related phenotype may have been easier to observe in mice for two reasons: First, mice were subjected to conflict tests to elicit the increased anxiety-related behavior, whereas human studies relied on questionnaires. Second, the anxiety-related phenotype was only present in mice homozygous for the Met allele, which suggested that association studies that focused primarily on humans heterozygous for the Met allele may not detect an association. In this context, another human genetic polymorphism in the serotonin transporter (5HTLPR) is associated with depression only in homozygote subjects with past trauma histories.