By contrast, Brennand et al. (2011) took a more generalized approach and generated hiPSC-derived neurons from four SZ patients who lacked a unifying genotype, but were selected on the basis of the likelihood of a genetic component to their disease (as supported by relatives affected by psychiatric disease or early age of onset). The group generated a mix of excitatory, inhibitory, and dopaminergic neurons, evidenced by the presence of VGLUT1, GAD67, and tyrosine hydroxylase, respectively. These patient-derived neurons formed fewer processes, exhibited decreased neuronal connectivity (assayed by trans-neuronal spread of rabies virus) and decreased spine density (Brennand et al., 2011). Most strikingly, many of the gene expression pathways perturbed in SZ hiPSC neurons were also detected in immature neural progenitor cells, indicating that these pathways were altered even before the establishment of post-mitotic neurons (Brennand et al., 2015). Overall, these findings mimic the decreased neuronal connectivity and synaptic function shown in post-mortem tissue studies (16, 33–35).
