Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety- like behavior in female mice

Background—Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach—As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results—Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxietylike behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxietylike behaviors during the estrus phase. © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. Corresponding Author, Francis S. Lee, Department of Psychiatry, Weill Cornell Medical College, 1300 York Ave, New York, NY 10065, [email protected], Tel: (212) 746-3169. *equal contribution Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The authors report no biomedical financial interests or potential conflicts of interest. NIH Public Access Author Manuscript Biol Psychiatry. Author manuscript; available in PMC 2013 September 15. Published in final edited form as: Biol Psychiatry. 2012 September 15; 72(6): 499–504. doi:10.1016/j.biopsych.2012.03.032. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Conclusions—These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans.