A major reason for identifying the genetic basis of a psychiatric disorder is to develop platforms for understanding disease mechanisms at a cellular-molecular level and accelerate therapeutic development. Despite the potential limitations of studying psychiatric disease in model organisms, mouse models of large-effect-size or Mendelian risk genes for ASD appear promising (56, 57). Many show large behavioral or cognitive deficits relative to wild-type littermates, as well as cellular or physiological phenotypes that may underlie disease pathophysiology. In parallel, advances in stem cell biology now make it possible to generate and study human neurons and their development in vitro (58), providing a platform for drug discovery and phenotypic screening. However, significant challenges exist, including the potential for in vitro artifacts, rigorous definition of cell types, or matching to in vivo brain development. The few studies examining monogenic forms of psychiatric disease via induced pluripotent stem cell–derived neurons are very encouraging (59–61), but consist of relatively small sample sizes. Integrating in vivo modeling in model organisms with in vitro modeling based on tissues derived from human stem cells will help balance the limitations of each system alone.
