The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models

The NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia is supported by multiple lines of evidence. Notably, administration of the NMDAR antagonist, ketamine, to healthy human subjects has psychotogenic action, producing both positive and negative symptoms associated with schizophrenia. NMDARs have multiple subtypes, but the subtypes through which ketamine produces its psychotogenic effects are not known. Here we address this question using quantitative data that characterize ketamine's ability to block different NMDAR subtypes. Our calculations indicate that, at a concentration that has psychotogenic action in humans, ketamine blocks a substantial fraction of GluN2C subunit-containing receptors but has less effect on GluN2A-, GluN2B-, and GluN2D-containing receptors. Thus, GluN2C-containing receptors may have preferential involvement in psychotic states produced by ketamine. A separate line of experiments also points to a special role for GluN2C. That work demonstrates the ability of NMDAR antagonists to mimic the elevation in the awake-state delta frequency EEG power that occurs in schizophrenia. Physiological experiments in rodents show that NMDAR antagonists generate delta oscillations by their action on the GluN2C-containing NMDARs that are prevalent in the thalamus. Optogenetic experiments suggest that such oscillations could contribute to symptoms of schizophrenia.