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

Notaras, M., Du, X., Gogos, J., van den Buuse, M., and Hill, R.A. (2017) The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair. Translational Psychiatry, 7.

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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 (hBDNF(Val66Met)) 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 hBDNF(Met/Met) mice had a depression-like phenotype in the FST irrespective of CORT, hBDNF(Val/Val) wildtype 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 hBDNF(Val/Val) group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNF(Val/Val) mice as a result of CORT treatment, which mimicked expression levels of hBDNF(Met/Met) mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNF(Val/Val) mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression.

Item ID: 51164
Item Type: Article (Research - C1)
ISSN: 2158-3188
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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Funders: University of Melbourne (UM), National Health and Medical Research Council (NHMRC), Australian Research Council (ARC), National Alliance for Research on Schizophrenia and Depression (NARSAD)
Date Deposited: 11 Oct 2017 07:44
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110199 Medical Biochemistry and Metabolomics not elsewhere classified @ 60%
11 MEDICAL AND HEALTH SCIENCES > 1117 Public Health and Health Services > 111714 Mental Health @ 40%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 100%
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