Abstract
Development of iPS cell technology has made it possible to prepare neural stem cells and neuronal cells from iPS cells, and made it feasible to examine pathogenic and pathological hypotheses of schizophrenia using patient’s samples. We focused on the neurodevelopmental abnormality hypothesis that is supported as the vulnerability basis of schizophrenia. To obtain insight into abnormalities in neurodevelopmental trajectories of schizophrenia, analyses of patient-derived human iPS cells (hiPSCs) should be informative. We established hiPSCs from two schizophrenia patients with the 22q11.2 deletion, and examined the molecular pathology of microRNA (miRNA) related to abnormality of neuronal differentiation/development. Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38, and conformingly the levels of p38 were up-regulated in the patient-derived cells. Furthermore, we confirmed an elevated expression of gliogenic (astrocyte) marker in postmortem brains from schizophrenia patients. These results suggest that a dysregulated balance of neurogenic and gliogenic competences may underlie schizophrenia.
