Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia.

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.

Study at a glance

Abstract

NMDA antagonists provide the best pharmacological model of psychosis-related schizophrenia. Data from circuit analysis of the effects of the antagonism of NMDA receptors in the CA1 region of the hippocampus of rats in vitro suggest a hypothesis concerning cortical circuit dysfunction responsible for NMDA antagonist-dependent psychosis, relevant to the psychosis associated with schizophrenia. The NMDA antagonists may act by causing a selective, partial, disinhibition of cortical projection cells. The effects are partially due to the partial role of NMDA-dependent transmission in the excitatory glutamate drive of interneurons. Characterization of the selectivity is incomplete, but includes disinhibition of the recurrent inhibitory circuit and is concentration-sensitive. It may result from differences in NMDA receptors (NMDARs) on interneurons. At higher concentrations, antagonism of all NMDA-dependent transmission results in anesthesia. At low concentration, selective blockade of NMDA-dependent LTP of the recurrent inhibitory circuit may disrupt particular aspects of information processing involving learning and/or memory, consistent with the generation of abnormal associations. An endogenous peptide, NAAG, is shown to antagonize NMDARs in a manner similar to known psychotogenic agents like ketamine or phencyclidine. Finally, mechanisms that could enhance NMDAR function are discussed as possible therapeutic strategies for psychosis.