Increased Cortical Excitability as a Critical Element in Schizophrenia Pathophysiology

The identification of schizophrenia predisposing genes critical for brain development and synaptic transmission has highlighted the developmental aspects of this disorder. Yet, symptoms typically emerge after adolescence, and environmental factors (both perinatally and during adolescence) also play a role in schizophrenia. As cortical interneurons have repeatedly been identified as abnormal in schizophrenia and these neurons and their dopamine innervation mature late (i.e., during adolescence), it is possible that early insults may affect these neurons but symptoms appear when interneurons should have matured. Abnormal interneuron activity, in particular in the prefrontal cortex, would increase cortical network activity, impairing information processing and the filtering of weak inputs (increasing “noise”). The specific profile of NMDA glutamate receptors cortical interneuron express may make them vulnerable to the effects of non-competing antagonists; in that way, the glutamate and GABA hypotheses of schizophrenia may converge by blockade of NMDA receptors in interneurons being responsible for symptoms. This specific distribution of NMDA receptor subtypes may allow the search of interneuron-targeting novel pharmacological tools, opening the possibility to restore balance in cortical networks.