Notaras, Michael J., Hill, Rachel A., Gogos, Joseph A., and van den Buuse, Maarten (2017) BDNF Val66Met genotype interacts with a history of simulated stress exposure to regulate sensorimotor gating and startle reactivity. Schizophrenia Bulletin, 43 (3). pp. 665-672.

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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 BDNFVal66Met (hBDNF(Val66Met)) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term 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(Val/Met) genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNF(Met/Met) and hBDNF(Val/Val) genotype mice. At the 30 ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNF(Val/Met) heterozygote mice but not hBDNF(Val/Val) or hBDNF(Met/Met) mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNF(Val/Val) male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype.

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