Hongjun Song, from Johns Hopkins University School of Medicine, generated hiPSC-derived cortical neurons from four members of a SZ family pedigree defined by a deletion mutation of DISC1 gene (4-base-pair frameshift deletion on exon 12) (Chiang et al., 2011), observing decreased excitatory postsynaptic current (EPSC) frequencies and synaptic vesicle protein 2 (SV2) puncta density in patients with the mutation, which were rescued by both transcription activator-like effector nucleases (TALEN)-mediated genetic correction (Wen et al., 2014). Subsequent RNA sequencing showed DISC1-associated changes in expression of genes involved in neuronal development, synaptic transmission, and those related to mental disorders. Complementary data obtained from genetically modified mice with this same DISC1 mutation highlighted the continued value of mouse models to study the role of specific mutations independent of genetic background, as a means of cross-paradigm validation of results obtained with hiPSCs, at the levels of neuronal circuits and behavior, and for in vivo drug testing.
