Neuronal nitric oxide synthase is permanently decreased in the cerebellum of rats subjected to chronic neonatal blockade of N-methyl-D-aspartate receptors

Pharmacological blockade of the (NMDA) receptor at critical stages of brain development may have long-lasting effects on brain chemistry and on animal behavior. We report here experiments in which the competitive NMDA recepto r antagonist CGP 39551 was administered to rat pups from postnatal day 7 (P 7) to P18. The stage of treatment was selected to primarily target the cere bellum, whose granule cells undergo post-mitotic migration and establishmen t of synaptic connections during this period. We focused our study on the l ong-term consequences of CGP 39551 treatment on the neuronal isoform of nit ric oxide synthase (nNOS) since nNOS is highly expressed in the cerebellum and it is functionally linked to the NMDA receptor. Treated rats exhibited a long-lasting (up to P70) decrease in the intensity of nNOS immunocytochem ical staining in the cerebellar cortex accompanied by a decrement of calciu m-dependent NOS catalytic activity. A comparable decrease of enzyme activit y was measured in the cerebral cortex, but not in the hippocampus, of adult rats. Other neurochemical markers (glutamatergic, gabaergic, purinergic) a nd glutamine synthetase were unchanged, while a cholinergic marker was slig htly increased in the cerebellum of CGP 39551 treated animals. Taken togeth er these data show that blockade of NMDA receptor during the critical perio d of formation and stabilization of neuronal circuits preferentially affect s long-term nNOS expression and catalytic activity in the cerebellum. (C) 1 998 Elsevier Science Ireland Ltd. All rights reserved.