[Abstract Title]. - Society for Neuroscience

NIH Grant MH082528
NIH Grant NS052819
Title: BDNF variant Val66Met regulates brain function in female mice in an estrous cycledependent
manner
Authors: *J. L. SPENCER 1 , E. M. WATERS 1 , T. A. MILNER 1,2 , F. S. LEE 2 , B. S.
MCEWEN 1 ;
1 Lab. Neuroendocrinol, Rockefeller Univ., New York, NY; 2 Weill Cornell Med. Col., New
York, NY
Abstract: 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 activitydependent
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.
Disclosures: J.L. Spencer , None; E.M. Waters, None; T.A. Milner, None; B.S. McEwen,
None; F.S. Lee, None.