title: Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.
abstract: Adult exposure to NMDA receptor antagonists, such as ketamine, produces psychosis in humans, and exacerbates symptoms in schizophrenic patients. We recently showed that ketamine activates the innate immune enzyme NADPH-oxidase in brain, and that the superoxide produced leads to dysfunction of a subset of fast-spiking inhibitory interneurons expressing the calcium-binding protein parvalbumin (PV). Here we show that neuronal production of interleukin-6 (IL-6) is necessary and sufficient for ketamine-mediated activation of NADPH-oxidase in brain. Removal of IL-6 in neuronal cultures by anti-IL-6 blocking antibodies, or in vivo by use of IL-6-deficient mice, prevented the increase in superoxide by ketamine and rescued the interneurons. Accumulating evidence suggests that schizophrenia patients suffer from diminished antioxidant defenses, and a recent clinical trial showed that enhancing these defenses may ameliorate symptoms of the disease. Our results showing that ketamine-induced IL-6 is responsible for the activation of NADPH-oxidase in brain suggest that reducing brain levels of this cytokine may protect the GABAergic phenotype of fast-spiking PV-interneurons and thus attenuate the propsychotic effects of ketamine.
authors.affiliation: Department of Medicine, Division of Geriatric Medicine, University of California, San Diego, La Jolla, California 92093-0746, USA. mbehrens@ucsd.edu
authors.forename: M Margarita
authors.initials: MM
authors.lastname: Behrens
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: Laura L
authors.initials: LL
authors.lastname: Dugan
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000906:Antibodies; D015850:Interleukin-6; D012333:RNA, Messenger; D013481:Superoxides; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D019255:NADPH Oxidases