BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function

Abstract

Natural fluctuations in circulating estradiol are associated with behavioral changes, including severe disturbances in mood and cognition in some women. Common genetic variation in some of the molecular mediators of estradiol effects on these behaviors, in brain regions such as the hippocampus, may explain individual variation in estradiol effects on behavior. We tested whether the common human variant BDNF Val66Met interacts with estradiol in the control of hippocampal function in cycling female mice homozygous for the wild-type Val or BDNF Met variant. BDNF Met increased anxiety behavior, impaired memory, and increased expression of BDNF and its receptor TrkB in the hippocampal formation. BDNF Met also dramatically altered the fluctuation of spatial memory, hippocampal Akt phosphorylation, and PSD-95 protein expression across the estrous cycle. The variant BDNF Val66Met should therefore be considered as a strong candidate for mediating genetic differences in ovarian steroid-related behavioral changes and disorders.

Fig. 1.

BDNF Val66Met impairs memory. OP and OR performance is represented by the novel object fraction, where chance performance (0.5) is indicated by a dotted line. (A) OR performance using an easy object pair. (B) OR performance using a more difficulty object pair. (C) OP performance on a test with 5-minute intertrial delay. *, P < 0.05 relative to chance. n = 8 for OP; 5 for OR. Error bars represent SEM.

Fig. 2.

BDNF Val66Met affects nonmnemonic behaviors in female mice. (A) Diagram of the path of one representative mouse of each genotype during a sample trial of the OR test. The two small white squares at the bottom of the field represent objects, and the larger white square represents the defined center of the open field. (B) Anxiety-type behavior measured as time in the center during the sample trials of both OP and OR tests. (C) Exploratory behavior measured as total object exploration during the sample trials of both OP and OR tests. *, P < 0.05 relative to Val. n = 8 for OP; 5 for OR. Error bars represent SEM.

Fig. 3.

Estrous cycle and BDNF genotype interact to control OP performance. (A) Performance of Val and Met mice on the OP task in different estrous cycle stages. Anxiety-type (B) and exploratory (C) behavior from the sample trial in different estrous cycle stages. *, P < 0.05 relative to chance. n = 8. Error bars represent SEM.

Fig. 4.

BDNF Met mice have increased hippocampal BDNF and TrkB expression. (A) Optical density of BDNF mRNA in the CA3 pyramidal cell layer (box) from in situ hybridization films. (B) Optical density of TrkB mRNA in the CA1 pyramidal cell layer (box) from in situ hybridization films. *, P < 0.05 for genotype. n = 6 for Val proestrus, 4 for Val diestrus, 5 for Met proestrus, and 4 for Met diestrus. Error bars represent SEM. (Scale bars: 100 μm.)

Fig. 5.

Estrous cycle fluctuation of pAkt-ir and PSD-95-ir is altered in BDNF Met/Met mice. pAkt-ir (A) and PSD-95-ir (B) in the CA1 stratum radiatum, CA3 stratum radiatum, and dentate hilus. *, P < 0.05 compared to diestrus. SR, stratum radiatum; DG HIL, hilus of the dentate gyrus. Error bars represent SEM. (Scale bars: 100 μm.)