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The Journal of Neuroscience, December 17, 2008, 28(51):13957-13966; doi:10.1523/JNEUROSCI.4457-08.2008

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Development/Plasticity/Repair
Interleukin-6 Mediates the Increase in NADPH-Oxidase in the Ketamine Model of Schizophrenia

M. Margarita Behrens,1 Sameh S. Ali,1 and Laura L. Dugan1,2

1Department of Medicine, Division of Geriatric Medicine, and 2Department of Neuroscience, University of California, San Diego, La Jolla, California 92093-0746

Correspondence should be addressed to either M. Margarita Behrens or Laura L. Dugan, Department of Medicine, Division of Geriatric Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0746. Email: mbehrens{at}ucsd.edu or Email: ladugan{at}ucsd.edu

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.

Key words: schizophrenia; interleukin-6; parvalbumin; interneurons; NADPH-oxidase; prelimbic

Received Sept. 17, 2008; revised Oct. 27, 2008; accepted Nov. 12, 2008.

Correspondence should be addressed to either M. Margarita Behrens or Laura L. Dugan, Department of Medicine, Division of Geriatric Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0746. Email: mbehrens{at}ucsd.edu or Email: ladugan{at}ucsd.edu






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