SCZ affects more than 21 million patients worldwide.67 Diagnosis is made when a patient presents with at least 6 months of perturbed language, perception, thinking, social activity, affect and volition. First-line treatments include atypical antipsychotics, such as olanzapine and risperidone. SCZ was among the first neuropsychiatric disorders modeled with patient iPSC-derived neurons.40, 68 In one of those studies, SCZ-iPSC-derived neurons showed decreased connectivity, synapses, spine density and expression of glutamate receptors when co-cultured with human astrocytes.40 Interestingly, treatment with the dopaminergic antagonist loxapine, but not clozapine, olanzapine, risperidone or thioridazine, during the last 3 weeks of neuronal differentiation increased neuronal connectivity in iPSC-derived neurons from all patients. The inability of the structurally similar antipsychotic clozapine to rescue phenotypes observed in defective neurons raises the question about the exact mechanism by which loxapine acts in this system. Another group generated iPSC lines from family members carrying mutant DISC1 and demonstrated synaptic defects in those iPSC-derived neurons.33 Genes related to synaptic transmission and development were dysregulated, about 90 of which had been previously linked to mental disorders, including depression, BPD and SCZ. Intriguingly, using gene editing techniques, the group established a causal link between the DISC1 mutation and the observed defects.33
