Probing the molecular and cellular pathological mechanisms of schizophrenia using human induced pluripotent stem cell models

With recent advancements in psychiatric genomics, as a field, “stem cell-based disease modelers” were given the exciting yet daunting task of translating the extensive list of disease-associated risks into biologically and clinically relevant information in order to deliver therapeutically meaningful leads and insights. Despite their limitations, human induced pluripotent stem cell (iPSCs) based models have greatly aided our understanding of the molecular and cellular mechanisms underlying the complex etiology of brain disorders including schizophrenia (SCZ). In this review, we summarize the major findings from studies in the past decade which utilized iPSC models to investigate cell type-specific phenotypes relevant to idiopathic SCZ and disease penetrant alleles. Across cell type differences, several biological themes emerged, serving as potential neurodevelopmental mechanisms of SCZ, including oxidative stress and mitochondrial dysfunction, depletion of progenitor pools and insufficient differentiation potential of these progenitors, and structural and functional deficits of neurons and other supporting cells. Here, we discuss both the recent progress as well as challenges and improvements needed for future studies utilizing iPSCs as a model for SCZ and other neuropsychiatric disorders.