BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity

Abstract

Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNF Val66Met (hBDNF Val66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the longterm effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30 ms and 100 ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100 ms ISI identified that, irrespective of CORT treatment, the hBDNF

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

“…Specifically, we previously replicated a gene-dosage effect of the hBDNF Met/Met genotype on fear conditioned memory and short-term spatial memory which we found could be ‘rescued’ by chronic CORT, 31 while in other behavioral paradigms, such as prepulse inhibition, chronic CORT exposure unveiled a heterozygote disadvantage phenotype among hBDNF Val/Met mice relative to both homozygous genotype groups. 37 In this respect, we can confirm that for behavioral despair on the FST an effect of hBDNF Val66Met genotype emerges at baseline, and that chronic CORT exposure induces a deficit among hBDNF Val/Val mice, while having no further effect on hBDNF Val/Met mice or hBDNF Met/Met mice (see Figure 1 ). Thus, hBDNF Met/Met mice perform on the FST similarly to CORT-treated hBDNF Val/Val mice, implicating that the Val66Met variant induces vulnerability to behavioral despair.…”

“…Sampling was based on our prior investigations using this mouse line, which have been adequately powered to detect medium-to-large as well as more subtle effects upon pooling (see below; refs. 31 , 37 ). Data analysis was undertaken using the IBM SPSS and Graphpad Prism packages.…”

“…As no significant interaction involving the main effect of sex was observed on any given behavioral or molecular measure, denoting no effect of sex on the main effects of genotype and treatment, data from male and female mice were analyzed together to increase power as consistent with previous investigations. 31 , 37 No exclusion criteria were applied, except for outliers (defined as values falling outside of ± 2 s.d.). Statistical significance was set at P =0.05, as per Fisher’s tables, while all between-group comparisons were corrected for multiple comparisons using Tukey’s or Holm-Sidak’s method depending on observed power.…”

The BDNF Val 66 Met polymorphism is associated with structural neuroanatomical differences in young children

“…As noted above, given the low frequency of the Met allele, we collapsed Val/Met and Met/Met individuals into one group: Met carriers (Petryshen et al , 2010, Tost et al , 2013, Yang et al , 2012, Ziegler et al , 2013), which is a common practice in the studies of this polymorphism in specific and low-MAF variants in general. But see recent work on differences between Val/Met and Met/Met animal models (Notaras et al , 2016). …”

Dissecting a Genomic Role of BDNF in Schizophrenia and Psychosis

“…The tools required to dissect the effect of BDNF variants on psychosis endophenotypes using rodents are thus available and awaiting application to guide clinical research. 32 In closing, a role for BDNF in schizophrenia seems likely; however, a genomic effect remains contentious. While BDNF gene variants are not likely to be major risk factors for schizophrenia in isolation, based on a lack of effect in large consortia studies, this does not rule out the possibility that BDNF variants may modify clinical aspects of the disorder by modulating BDNF availability or function.…”