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

• Published in: Translational psychiatry Vol. 7; no. 9; p. e1233
• Main Authors: Notaras, M, Du, X, Gogos, J, van den Buuse, M, Hill, R A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.09.2017; Nature Publishing Group
• Subjects: 631/378/340; 64/110; 692/699/476/1414; 82/1; Animals; Behavior; Behavior, Animal - drug effects; Behavior, Animal - physiology; Behavioral Sciences; Biological Psychology; Brain-Derived Neurotrophic Factor - genetics; Corticosterone - pharmacology; Depression - chemically induced; Depression - genetics; Depression - physiopathology; Disease Models, Animal; Hippocampus - drug effects; Hippocampus - metabolism; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Neurosciences; Original; original-article; Pharmacotherapy; Polymorphism, Single Nucleotide; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Psychiatry; Resilience, Psychological - drug effects; Rodents; Stress, Psychological - chemically induced; Stress, Psychological - genetics; Stress, Psychological - physiopathology
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2017.205

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 BDNF Val66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression.