title: The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses.
abstract: Subanesthetic doses of NMDA receptor antagonist ketamine induce schizophrenia-like symptoms in humans and behavioral changes in rodents. Subchronic administration of ketamine leads to loss of parvalbumin-positive interneurons through reactive oxygen species (ROS), generated by the NADPH oxidase NOX2. However, ketamine induces very rapid alterations, in both mice and humans. Thus, we have investigated the role of NOX2 in acute responses to subanesthetic doses of ketamine. In wild-type mice, ketamine caused rapid (30 min) behavioral alterations, release of neurotransmitters, and brain oxidative stress, whereas NOX2-deficient mice did not display such alterations. Decreased expression of the subunit 2A of the NMDA receptor after repetitive ketamine exposure was also precluded by NOX2 deficiency. However, neurotransmitter release and behavioral changes in response to amphetamine were not altered in NOX2-deficient mice. Our results suggest that NOX2 is a major source of ROS production in the prefrontal cortex controlling glutamate release and associated behavioral alterations after acute ketamine exposure. Prolonged NOX2-dependent glutamate release may lead to neuroadaptative downregulation of NMDA receptor subunits.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva University Hospitals, CH-1211 Geneva, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sorce
authors.forename: Stefania
authors.initials: S
authors.lastname: Schiavone
authors.forename: Paolo
authors.initials: P
authors.lastname: Tucci
authors.forename: Marilena
authors.initials: M
authors.lastname: Colaianna
authors.forename: Vincent
authors.initials: V
authors.lastname: Jaquet
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cuomo
authors.forename: Michel
authors.initials: M
authors.lastname: Dubois-Dauphin
authors.forename: Luigia
authors.initials: L
authors.lastname: Trabace
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D007649:Ketamine / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017397:Prefrontal Cortex / Q000201:enzymology / Q000378:metabolism; D011605:Psychoses, Substance-Induced / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D007649:Ketamine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases