Beyond Phenotype: The Promise of hiPSC-Based Studies of Schizophrenia.

Schizophrenia (SCZD) is a heritable developmental disorder. While the molecular mechanism of disease remains unclear, insights into the disorder have been made through a vast array of experimental techniques. Together, MRI brain imaging, pharmacological and postmortem pathological studies have observed decreased brain volume, aberrant neurotransmitter signaling, reduced dendritic arborization and impaired myelination in SCZD. Genome wide association studies have identified common variants 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 towards SCZD, even without knowledge of the genes interacting to produce the disease state. SCZD hiPSC neurons show cellular defects comparable to those identified in postmortem human and mouse studies, and gene expression changes 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.