Concise Review: The Promise of Human Induced Pluripotent Stem Cell-Based Studies of Schizophrenia

Abstract

Schizophrenia (SCZD) is a heritable developmental disorder. Although the molecular mechanism of disease remains unclear, insights into the disorder have been made through a vast array of experimental techniques. Together, magnetic resonance brain imaging, pharmacological, and post-mortem pathological studies have observed decreased brain volume, aberrant neurotransmitter signaling, reduced dendritic arborization, and impaired myelination in SCZD. Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms as well as rare copy number variants that contribute to SCZD, while mouse models of candidate SCZD genes show behavioral abnormalities and anatomical perturbations consistent with human disease. The advent of human induced pluripotent stem cells (hiPSCs) makes it possible to study SCZD using live human neurons with a genetic predisposition toward SCZD, even without knowledge of the genes interacting to produce the disease state. SCZD hiPSC neurons show cellular defects comparable to those identified in post-mortem human and mouse studies, and gene expression changes are consistent with predictions made by GWAS. SCZD hiPSC neurons represent a new tool to look beyond phenotype and begin to dissect the molecular mechanisms of SCZD.