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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.

SUBMITTER: Behrens MM

PROVIDER: S-EPMC2752712 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.

Behrens M Margarita MM Ali Sameh S SS Dugan Laura L LL

The Journal of neuroscience : the official journal of the Society for Neuroscience 20081201 51

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 ketami ...[more]

PMID: 19091984

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Dataset Information

Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.

Publications

Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.

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