Developmental GABAergic deficit enhances methamphetamine-induced apoptosis

Abstract

Neuroanatomical evidence suggests that GABAergic deficits and progressive cortical atrophy occur with schizophrenia. To evaluate the hypothesis that neurodevelopmental deficits affect neurodegeneration occurring with schizophrenia, this study examined a novel animal model for schizophrenia-related neurodevelopmental GABAergic deficit in neurodegenerative progression. The prenatal N-methyl-D-aspartate (NMDA) receptor hypofunction model that induces neurodevelopmental GABAergic deficit in the medial prefrontal cortex (mPFC) was used to examine whether adult offspring of Sprague-Dawley rats exhibited disruption of prepulse inhibition (PPI), enhancement of methamphetamine (METH) (2.5 mg/kg)-induced glutamate release in the mPFC and the emergence of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive neurons in this brain region. Offspring of dams exposed to NMDA receptor antagonist MK-801 on days 15-18 of pregnancy (MK-801 offspring) showed reduced density of parvalbumin-immunoreactive GABAergic interneurons in the mPFC, PPI disruption on postnatal days 63 (P63) and 35 (P35) and an enhanced METH (2.5 mg/kg)-induced glutamate release. Repeated administration of this psychostimulant increased the emergence of TUNEL-positive cells. These findings suggest that prenatal blockade of NMDA receptors induces a neurodevelopmental GABAergic deficit. The decrease in the density of GABAergic neurons might be related to disruption of sensorimotor gating (PPI), enhanced METH-induced release of glutamate in the mPFC and a repeated METH injection-induced increase in apoptosis in this region of the brain in adult animals.