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.
NMDA antagonists, such as ketamine and phencyclidine, produce psychosis-like effects that model schizophrenia. Circuit analysis in rats shows these drugs selectively disinhibit cortical projection cells in the hippocampus by partially blocking NMDA receptors on interneurons, disrupting the recurrent inhibitory circuit. At low concentrations, this blockade impairs learning and memory, potentially generating abnormal associations. The endogenous peptide NAAG antagonizes NMDA receptors similarly. Enhancing NMDA receptor function is discussed as a possible therapeutic approach for psychosis.