Modeling developmental neuropsychiatric disorders with iPSC technology: challenges and opportunities

•Considerations for choosing and making the appropriate cell types to model neuropsychiatric disease.•Understanding the sources of variability in iPSC models of neurodevelopmental disorders, and considerations for minimizing or bypassing this variability.•Challenges to modeling neuropsychiatric disease of known strong genetic influence versus idiopathic disease.•Managing expectations in identifying cellular phenotypes in vitro.

The development of cellular reprogramming methods to generate human induced pluripotent stem cells (iPSC) has led to the establishment of lines from hundreds of patients with a variety of neurologic and psychiatric diseases. One of the fundamental powers of iPSC technology lies in the competency of these cells to be directed to become any cell type in the body, thus allowing researchers to examine disease mechanisms and identify and test novel therapeutics in relevant cell types. The field has now exited the phase of 'proof-of-principle' studies showing the potential of the model systems, and it has now entered an exciting new era where iPSC studies are contributing to the field's understanding of mechanisms of disease. Here, we describe the challenges of iPSC modeling of neuropsychiatric disorders, and highlight studies where some of these challenges have been addressed to provide novel insights into disease mechanisms.