NMDA receptor regulation of memory and behavior in humans

Reduced activity of NMDA receptors in the brain, which can be experimentally induced by antagonist drugs, impairs memory by disrupting the encoding and consolidation of information into long-term storage. More severe NMDA receptor hypofunction produces symptoms resembling psychosis and dissociation, and sustained underactivation triggers a neurotoxic process with distinct neuropathological features. As the brain ages, NMDA receptor function naturally declines, contributing to age-related memory and learning deficits. Preventing NMDA receptor hypofunction or its downstream effects may offer therapeutic strategies for memory and behavioral dysfunction in neuropsychiatric conditions.

Study at a glance

Abstract

N-methyl-D-aspartate (NMDA) receptor hypofunction is associated with a range of effects on cognition and behavior in whole animal and human studies. NMDA receptor hypofunction within the brain, which can be induced experimentally in vivo using NMDA receptor antagonist drugs, produces adverse effects on memory function. The results suggest that NMDA receptor hypofunction can preferentially affect neural mechanisms regulating the efficiency of encoding and consolidation into longer-term storage. More pronounced NMDA receptor hypofunction can produce a clinical syndrome that includes core features of psychosis, as well as dissociation. Finally, sustained and severe underexcitation of NMDA receptors in the adult brain is associated with a neurotoxic process with well-characterized neuropathological features. Progressive increases in severity of NMDA receptor hypofunction within the brain can produce a range of effects on brain function, involving local and distributed circuitry, which may underlie the observed changes in behavior. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, potentially contributing to further age-related decreases in memory and learning performance. Pharmacological and genomic methods for preventing NMDA receptor hypofunction, or for preventing the upstream or downstream consequences modeled by treatment with NMDA antagonists, may be applicable to the prevention and treatment of memory and behavioral dysfunction in a variety of neuropsychiatric disease conditions.