Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex. Recent data suggest that IFITM3 expression is a critical mediator of maternal immune activation. As the IFITM gene family is primarily expressed in the endothelial cells and meninges, and as the meninges play a critical role in interneuron development, we suggest that these two non-neuronal cell populations might play an important role in the disease pathophysiology. Finally, we propose that IFITM3 in particular might be a novel, appealing, knowledge-based drug target for treatment of schizophrenia. Gene*environment interactions play a critical role in the emergence of schizophrenia pathophysiology. Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease (1-3) and it is likely that these immune changes actively contribute to disease symptoms (1, 4, 5). Regardless of the abundance of data obtained to date, our understanding of the mechanism by which the immune system disturbances arise is limited: we do not have a good insight into the origin or sequence of events by which the immune dysregulation develops, and to date we have not taken full advantage of these changes as potential therapeutic targets.

Reduced expression of the GAD1 gene-encoded 67-kD protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the schizophrenia. GAD67 downregulation occurs in multiple interneuronal subpopulations, including the parvalbumin positive (PVALB+) cells. To investigate the role of the PV-positive GABA-ergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in GABA release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty seeking and reduced fear extinction. Furthermore, NMDA receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABA-ergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.