DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a complex neurodevelopmental disorder with high heritability. Years of research show that SCZ is not a monogenic disease but a network disease with multiple risk genes and environmental factors of small effects interacting with each other to produce the clinical phenotype. The same risk factors can be implicated in multiple diseases, stressing the importance of studying SCZ in a network context. Our central hypothesis is that there are shared pathogenetic gene networks that underlie the complex and heterogeneous interactions of risk factors. Identification of such shared SCZ gene networks will be essential for identifying shared therapeutic targets. Remarkable advances have been made in recent genetic studies with an increasing number of risk gene loci reaching genome-wide significance. However, functional effects of many of these loci have not been elucidated due to their presence outside of the coding regions. Thus, developmental brain tissues from control and SCZ patients will be instrumental in clarifying their effects on gene expression during SCZ pathogenesis, leading to mechanistic insights into SCZ gene network and etiology. To this end, we have successfully optimized the differentiation of iPSCs into Medial Ganglionic Eminence (MGE)-type interneurons, which are one of the most consistently affected neural types in SCZ. Interestingly, our preliminary transcriptome analysis has shown that a significantly affected gene ontology term in developing SCZ MGE-type interneurons was the immune response, suggesting interactions between SCZ genomic burden and immune activation. In accordance with these findings, there were enriched SCZ associations among immune genes in a recent large-scale GWAS. Furthermore, maternal infection during pregnancy has been associated with SCZ and maternal immune activation models exhibit SCZ-like postnatal behavioral and histopathological abnormalities, including those in interneurons. Thus, employing highly homogeneous and well-characterized Sox6+GABA+ MGE-type interneurons from controls and SCZ iPSCs, we will test our hypothesis of shared SCZ gene networks during pathogenesis by analyzing common disturbances in SCZ transcriptome during neurodevelopment and their interactions with immune activation. To minimize controllable sources of variability, we will limit our subjects to non-Hispanic Caucasian males with severe disease phenotypes (treatment-resistant SCZ that required Clozapine treatment). Uncovering shared gene networks by various SCZ risk factors during development will provide novel and systemic insights into SCZ pathogenesis, complementing SCZ genetic studies by allowing analysis of tissue-specific modes of gene mis-expression. This will also lead to novel therapeutic targets for preventive treatments, which will address the primary pathologic processes rather than merely control symptoms.

PUBLIC HEALTH RELEVANCE: Schizophrenia (SCZ) is a highly heritable neuro-developmental disorder, whose etiology and pathogenesis is beginning to be understood. Cortical interneurons are substantially affected in SCZ and the proposed study is aimed at identifying SCZ-specific functional gene networks affecting these cells during development. This study, using iPSC-derived highly homogeneous cell population, will not only help identify developmental mechanisms of SCZ but also will open the door to novel therapeutic approaches.