BDNF variant Val66Met regulates brain function in female mice in an estrous cycle-dependent manner.

Society for Neuroscience. 2008.


Brain-derived neurotrophic factor (BDNF) is critical for neuronal survival, growth, differentiation, and synaptic plasticity. The Val66Met variant of the human BDNF gene, found in 30% of Caucasians, is a point mutation in the coding sequence for the pro-region. Neurons expressing the Met variant show impaired trafficking of pro-BDNF and decreased activity-dependent BDNF secretion. Human Met carriers have decreased hippocampal activation and cognitive performance. Similarly, male mice expressing the Met variant have smaller hippocampi and impaired freezing during hippocampal-dependent fear conditioning. Clinical studies suggest that the Val66Met variant influences susceptibility to psychiatric and neurologic disease, but in a gender-dependent manner. These gender differences could stem from an interaction of the Met variant with ovarian steroids. In animal studies, estrogen (E) modulates BDNF expression and activation of its receptor TrkB, which may be necessary for E enhancement of hippocampal synaptic plasticity. We hypothesized that the Val66Met variant alters the natural regulation of brain function by ovarian steroids in female mice homozygous for the Val or Met variant. Ten V/V (wild-type) and 10 M/M mice were tested on the object placement and object recognition tests at four different phases of the estrous cycle (proestrus, estrus, diestrus 1, and diestrus 2). Brains of mice in proestrus or diestrus were examined for synaptic protein expression and TrkB activation. M/M animals exhibited enhanced anxiety behavior, as well as impaired object placement and object recognition behavior. On the object placement task, genotype differences in performance were dependent on estrous cycle phase, suggesting differential modulation by ovarian steroids in V/V and M/M animals. In agreement with our previous studies, V/V mice had increased TrkB activation and PSD-95 expression during proestrus (high E) relative to diestrus (low E). In M/M animals, only TrkB activation, but not increased PSD-95 expression, was observed during proestrus. This suggests that intact activity-dependent secretion of BDNF is necessary for ovarian steroid modulation of synaptic protein expression, but not for signaling through the TrkB receptor. We conclude that BDNF variant Val66Met modulates hippocampal function in female mice in an estrous-cycle dependent manner. The dependence of the effects of variant BDNF on estrous cycle stage suggest that in humans, this variant may interact with ovarian steroids to influence susceptibility to psychiatric and neurological disorders, particularly those disorders known to be influenced by the menstrual cycle.