Interaction of Brain-Derived Neurotrophic Factor Val66Met genotype and history of stress in regulation of prepulse inhibition in mice

Abstract

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism results in reduced activity-dependent BDNF release and has been implicated in schizophrenia. However, effects of the polymorphism on functional dopaminergic and N-methyl-d-aspartate (NMDA) receptor-associated activity remain unclear. We used prepulse inhibition, a measure of sensorimotor gating which is disrupted in schizophrenia, and assessed the effects of acute treatment with the dopamine receptor agonist, apomorphine (APO), and the NMDA receptor antagonist, MK-801. We used adult humanized hBDNF(Vall66Met) 'knockin' mice which express either the Val/Val, Val/Met or Met/Met genotype. An interaction of BDNF with stress was modelled by chronic young-adult treatment with corticosterone (CORT). At 1 or 3mg/kg, APO had no effect in Val/Val mice but significantly reduced PPI at the 100ms inter-stimulus interval (ISI) in Val/Met and Met/Met mice. However, after CORT pretreatment, APO significantly reduced PPI in all genotypes similarly. At 0.1 or 0.25mg/kg, MK-801 significantly disrupted PPI at the 100ms ISI independent of genotype or CORT pretreatment. There were differential effects of APO and MK-801 on PPI at the 30ms ISI and startle between the genotypes, irrespective of CORT pretreatment. These results show that the BDNF Val66Met Val/Met and Met/Met genotypes are more sensitive than the Val/Val genotype to the effect of APO on PPI. A history of stress, here modelled by chronic CORT administration, increases effects of APO in Val/Val mice.