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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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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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: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320599 Medical biochemistry and metabolomics not elsewhere classified @ 60%
42 HEALTH SCIENCES > 4203 Health services and systems > 420313 Mental health services @ 40%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 100%
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