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

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/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/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 hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/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 hBDNFVal/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.

Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders

“…It should be noted that, in terms of the two-hit hypothesis, there are studies which show that a second hit actually led to improvements, and some genetic polymorphisms, including BDNF Val66Met polymorphism, may actually increase resilience. For example, a recent study showed that BDNF Met/Met transgenic mice had spatial and fear-associated memory deficits, but corticosterone treatment recovered this phenotype ( Notaras et al, 2017 ).…”

The BDNF Val66Met polymorphism affects negative memory bias in civilian women with PTSD

“…This finding suggests that chronic stress potentiates the fear circuitry into adulthood in the Met carriers, thereby increasing their susceptibility to fear-and anxiety-related psychiatric disorders such as PTSD 8,14 . With this transgenic mouse model, the same research group showed that the Val66Met polymorphism acts as a regulator of glucocorticoid-induced changes in stress sensitive molecules across corticohippocampal regions 15 . In line with this, a study investigated extinction of conditioned fear responses in genetic knock-in mice as well as humans in order to understand the effect of this polymorphism, demonstrating that the extinction learning was impaired in Met allele carriers relative to non-Met allele carriers for both mice and humans 16 .…”

Changes in neuroplasticity following early-life social adversities: the possible role of brain-derived neurotrophic factor

“…119 In another study, Val66Met mice that were subjected to the forced-swim test showed the phenotype of behavioural despair at baseline, which only appeared in Val/Val mice after chronic corticosterone administration during late adolescence. 120 Hippocampal memory function of Val66Met mice was also found to be more sensitive to glucocorticoid signalling. 121 Clinical data It has been postulated that Val66Met could convey an increased susceptibility to stress.…”