Heterogeneity in the etiopathology of neurodevelopmental disorders such as autism spectrum disorders (ASD) or schizophrenia (SCZ) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling neurodevelopmental disorders for studying complex neuronal phenotypes. In our work, we have generated iPSCs derived from an ASD patient or SCZ patients. To investigate disease specific cellular pathogenic mechanism, patient-specific iPSCs were differentiated into neuronal cells (induced neurons; iNs). The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function. We are investigating cellular phenotypes using SCZ-patient specific derived iPSCs. 

첨부: 뇌과학세미나 포스터