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

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.

NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex

“…We have previously reported that systemic administration of NMDA antagonists increases extracellular levels of glutamate in the PFC of awake animals (33,34). A disinhibition process, i.e., NMDA antagonistinduced blockade of ␥-aminobutyric acid (GABA) input to cortical glutamate afferents, is thought to result in this increase (10,33,35,36). In agreement with an enhancement in cortical glutamate release, functional imaging studies have shown an increase in metabolic activity in the human PFC after exposure to the NMDA antagonist ketamine (11,37).…”

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

“…Systemic administration of NMDA antagonists is thought to initiate a disinhibition process by inhibiting NMDA-mediated firing rate of gamma-aminobutyric acid (GABA) interneurons, resulting in increased firing rate of pyramidal neurons and glutamate release in the PFC (Jackson et al 2004;Moghaddam et al 1997;Olney 1990). The origin of glutamatergic projections on GABA neurons that are disinhibited by NMDA antagonist is not clear but may involve afferents from the hippocampus (Greene 2001). Pretreatment with CDPPB may reduce the extent of this disinhibition by "recruiting" more NMDA receptors that are activated by endogenous glutamate.…”

Dopaminergic and Glutamatergic Regulation of Effort- and Delay-Based Decision Making

“…In the present study, ketamine may have induced a similar effect, causing an overestimation of the delay to reward, which would be expected to further bias the animal's choice toward immediate/smaller rewards. These effects may be mediated in part through actions on the hippocampus, given that ketamine disrupts hippocampal functioning (Greene, 2001) and lesions of the hippocampus increase impulsive responding using a similar delaydiscounting procedure (Cheung and Cardinal, 2005). Further insight into the neural mechanism by which ketamine may alter delay-based decision making comes from neurophysiological studies in awake, behaving rats.…”