How Nox2-containing NADPH oxidase affects cortical circuits in the NMDA receptor antagonist model of schizophrenia.

SIGNIFICANCE: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). RECENT ADVANCES: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. CRITICAL ISSUES: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. FUTURE DIRECTIONS: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.