Neurobiology of schizophrenia onset

The clinical symptoms and cognitive and functional deficits of schizophrenia typically begin to gradually emerge during late adolescence and early adulthood. Recent findings suggest that disturbances of a specific subset of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV), which may regulate the course of postnatal developmental experience-dependent synaptic plasticity in the cerebral cortex, including the prefrontal cortex (PFC), may be involved in the pathogenesis of the onset of this illness. Specifically, converging lines of evidence suggest that oxidative stress, extracellular matrix (ECM) deficit and impaired glutamatergic innervation may contribute to the functional impairment of PV neurons, which may then lead to aberrant developmental synaptic pruning of pyramidal cell circuits during adolescence in the PFC. In addition to promoting the functional integrity of PV neurons, maturation of ECM may also play an instrumental role in the termination of developmental PFC synaptic pruning; thus, ECM deficit can directly lead to excessive loss of synapses by prolonging the course of pruning. Together, these mechanisms may contribute to the onset of schizophrenia by compromising the integrity, stability, and fidelity of PFC connectional architecture that is necessary for reliable and predictable information processing. As such, further characterization of these mechanisms will have implications for the conceptualization of rational strategies for the diagnosis, early intervention, and prevention of this debilitating disorder.