Modeling schizophrenia using induced pluripotent stem cell-derived and fibroblast-induced neurons

Abstract

Although schizophrenia affects a number of brain regions and produces a range of clinical symptoms, we believe its origins lie at the level of single neurons and simple networks. Owing to this, as well as to its high degree of heritability, we hypothesize that schizophrenia is amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or fibroblast-induced neurons, a limitless quantity of live human neurons can now be generated from patient skin biopsies. We predict that cell-based studies will ultimately contribute to our understanding of the molecular and cellular underpinnings of this debilitating disorder.

Fig. 1.

Cell-based modeling of psychiatric disorders. Fibroblast cells obtained from patients can be used to generate live human neurons with a genetic background known to produce the disease state. First, fibroblasts can be reprogrammed to hiPSCs by transient expression of OCT4, SOX2, KLF4, and c-MYC and then subsequently differentiated into NPCs and mature neurons. Second, fibroblasts can be directly converted to iNPCs by transient expression of SOX2 and then subsequently differentiated to neurons. Third, fibroblasts can be directly converted into a neuronal fate by transient expression of ASCL1, BRN2, MYT1L, and NEUROD.