NMDA receptor dysfunction in the developing prefrontal cortex in two animal models for schizophrenia

Schizophrenia is a highly debilitating illness often diagnosed in late adolescence and early adulthood following the emergence of psychotic symptoms. In addition to psychosis, negative symptoms and cognitive deficits are characteristic of the disorder, and are often evident prior to diagnosis. While positive symptoms are often attenuated with antipsychotic treatment, cognitive dysfunctions are unresponsive to therapeutic agents and persist throughout the course of the illness. As the best determinant of functional outcome, targeting the pathophysiology of cognitive deficits has become a priority for government agencies, academic research institutions, and the pharmaceutical industry. Among the prominent hypotheses attributed to schizophrenia, cortical hypofunction of the glutamate neurotransmitter system is an appealing possibility due to the importance of N-methyl-D-aspartate receptors (NMDARs), a type of ionotropic receptor, in brain development and cognition. Interestingly, blocking NMDARs during juvenile development is sufficient to elicit schizophrenia-like phenotypes in adult animals. Further, schizophrenic subjects display significant prefrontal hypofunction during performance of cognitive tasks. Compelled by the importance of the NMDAR system in the development and maturation of the prefrontal cortex, this work explores the expression profile and functional properties of the NMDAR system during juvenile and adolescent development in two animal models for schizophrenia: the neurodevelopmental MAM model and the inducible hDISC1 mutant mouse model. We confirm that NMDAR hypofunction is a feature of prefrontal development in these two models, albeit by changes in expression of divergent subunits. Further, we explore a mechanism by which NMDAR expression changes occur in the juvenile prefrontal cortex, implicating aberrant epigenetic regulation of the NR2B subunit. These data support the neurodevelopmental hypofunction hypothesis and highlight the importance of investigating early prefrontal dysfunction to understand the complex pathology observed in the chronic stage of schizophrenia.