As a proof-of-principle application, we investigated whether directed differentiation to hippocampal granule neurons could reveal disease-related phenotypes in the hiPSC model of SCZD, a neurodevelopmental disease in which hippocampus-associated cognitive impairments are highly conserved among the patient cohort (Tamminga et al., 2010, 2012). Studies using animal models and, more recently, postmortem brain tissue found evidence of pathophysiological alterations, termed the “immature dentate gyrus,” that were characterized by an increased number of calretinin-positive immature NPCs at the expense of calbindin-positive mature neurons in SCZD and bipolar patients (Yamasaki et al., 2008; Walton et al., 2012; Shin et al., 2013). These findings provide important insights into the hypothesized neurodevelopmental etiology of these neuropsychiatric diseases. However, the approaches used thus far have significant limitations. Examining postmortem tissue can only provide information at the end point of the disease and limits investigation of developmental aspects that may have led to this pathophysiology. Moreover, transgenic animal models can only reproduce some attributes of SCZD and cannot fully recapitulate the key genetic events associated with the pathogenesis of the disease. Using our differentiation approach, we generated
