RRC ID 68004
Author Lim CS, Kim MJ, Choi JE, Islam MA, Lee YK, Xiong Y, Shim KW, Yang JE, Lee RU, Lee J, Park P, Kwak JH, Seo H, Kim CH, Lee JH, Lee YS, Hwang SK, Lee K, Lee JA, Kaang BK.
Title Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice.
Journal Mol Psychiatry
Abstract Heterogeneity in the etiopathology of autism spectrum disorders (ASD) 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 ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. 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. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.
Volume 26(12)
Pages 7538-7549
Published 2021-12-1
DOI 10.1038/s41380-021-01216-9
PII 10.1038/s41380-021-01216-9
PMID 34253863
PMC PMC8873012
MeSH Animals Autism Spectrum Disorder* / metabolism Cell Adhesion Molecules / genetics* Humans Mice Mice, Knockout Mutation / genetics Neurons / metabolism Receptors, N-Methyl-D-Aspartate* / genetics Receptors, N-Methyl-D-Aspartate* / metabolism
IF 12.384
Mice RBRC05290