Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models

Abstract

Schizophrenia and related mental disorders are common and devastating conditions for which we have a limited understanding of their origin and mechanisms. Although this apparent lack of progress despite vast research efforts could be due to difficulties in reproducing the disease in animals, animal work is now providing important insight onto possible pathophysiological changes in the brain. Postmortem studies of human brains have provided data indicating altered local inhibitory circuits in the cerebral cortex in schizophrenia and different developmental, pharmacological, and genetic animal models converge in revealing deficits in cortical interneuron function that can be associated with neurophysiological and behavioral alterations resembling aspects of the disease. Schizophrenia pathophysiology has a complex developmental trajectory because overt symptoms become evident during late adolescence despite earlier events contributing to the disease. The late incidence of schizophrenia can be explained by the protracted maturation of brain circuits implicated in the disease, particularly during adolescence. Excitatory and inhibitory processes in cortical circuits are tightly modulated by dopamine (DA), and many aspects of DA function in cortical regions acquire their adult profile during adolescence. This maturation fails to occur or is abnormal in several different rodent models of schizophrenia, yielding a number of functional and behavioral deficits relevant to the disease. Thus, periadolescent changes in cortical inhibitory circuits are a critical developmental stage likely implicated in the transition to schizophrenia. These observations provide the foundation for novel research-based therapeutic approaches and perhaps will even lead to ways to prevent the progression of the disease in predisposed subjects.