Changes in NMDA receptor/nitric oxide signaling pathway in the brain with aging.

The N-methyl-D-aspartate (NMDA) receptor/nitric oxide (NO) signaling pathway plays an important role in neuronal plasticity. Previous studies with in vitro autoradiography showed that the number of NMDA receptor/ion channel complexes in the cerebral cortex and hippocampus is decreased by aging. Confocal laser scanning microscopy reveals circuit-specific alterations of NMDA receptor subunit 1 in the dentate gyrus of aged monkeys. Histochemistry for NADPH diaphorase (NADPH-d), a marker for neurons containing NO synthase (NOS), reveals that the number of NADPH-d-positive neurons in the cerebral cortex and striatum is significantly reduced from that in young rats. In the hippocampus, no age-related changes in NADPH-d staining are reported, while in situ hybridization histochemistry indicates an increase in the level of mRNA for neuronal NOS. NOS activity in the brain also appears to decrease with aging. These results suggest that the function of the NMDA receptor/NO signaling pathway in the brain is impaired by aging, and that dysfunction of this signaling pathway may underlie aging-associated memory impairment in rats.