Work

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

Year: 2017

Type: article

Abstract: The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Metmice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Valwildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Valgroup. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Valmice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Metmice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Valmice by CORT. This work establishes BDNFVal66Metgenotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression.

Source: Translational Psychiatry

DOI: 10.1038/tp.2017.205

Authors: M Notaras, X Du, J Gogos, M van den Buuse, R A Hill