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Postmortem and functional imaging studies of patients with psychiatric disorders, including schizophrenia, are consistent with a dysfunction of interneurons leading to compromised inhibitory control of network activity. Parvalbumin (PV)-expressing, fast-spiking interneurons interacting with pyramidal neurons generate cortical gamma oscillations (30-80 Hz) that synchronize cortical activity during cognitive processing. In postmortem studies of schizophrenia patients, these interneurons show reduced PV and glutamic acid decarboxylase 67 (GAD67), an enzyme that synthesizes GABA, but the consequences of this downregulation are unclear. We developed a biophysically realistic and detailed computational model of a cortical circuit including asynchronous release from GABAergic interneurons to investigate how reductions in PV and GABA affect gamma oscillations induced by sensory stimuli. Networks with reduced GABA were disinhibited and had altered gamma oscillations in response to stimulation; PV-deficient GABA synapses had increased asynchronous release of GABA, which decreased the level of excitation and reduced gamma-band activity. Combined reductions of PV and GABA resulted in a diminished gamma-band oscillatory activity in response to stimuli, similar to that observed in schizophrenia patients. Our results suggest a mechanism by which reduced GAD67 and PV in fast-spiking interneurons may contribute to cortical dysfunction in schizophrenia and related psychiatric disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]