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 δ frequency EEG power that occurs in schizophrenia. Physiological experiments in rodents show that NMDAR antagonists generate δ 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.
Department of Biology, Brandeis University, Waltham, Massachusetts 02454.
Elizaveta
0000-0002-6493-9055
E
Khlestova
Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Jon W
JW
Johnson
Departments of Psychiatry and Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, and.|Yale-New Haven Hospital, New Haven, Connecticut 06510.
John H
JH
Krystal
Department of Biology, Brandeis University, Waltham, Massachusetts 02454, lisman@brandeis.edu.
John
J
Lisman
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019317:Evidence-Based Medicine; D006213:Hallucinogens; D006801:Humans; D007649:Ketamine; D011605:Psychoses, Substance-Induced / Q000209:etiology / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*
D006213:Hallucinogens; C432823:NR2C NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
NMDA hypofunction hypothesis; channel block; delta oscillations; thalamus