Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.
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.
Behrens
M Margarita
MM
Department of Medicine, Division of Geriatric Medicine, University of California, San Diego, La Jolla, California 92093-0746, USA. mbehrens@ucsd.edu
Ali
Sameh S
SS
Dugan
Laura L
LL
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
D000906:Antibodies; D015850:Interleukin-6; D012333:RNA, Messenger; D013481:Superoxides; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D019255:NADPH Oxidases