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Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice
- Source :
- Molecular psychiatry. 26(12)
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
animal structures
Dendritic spine
Autism Spectrum Disorder
Biology
medicine.disease_cause
Receptors, N-Methyl-D-Aspartate
03 medical and health sciences
Cellular and Molecular Neuroscience
DSCAM
Mice
0302 clinical medicine
Downregulation and upregulation
medicine
Animals
Humans
Induced pluripotent stem cell
Molecular Biology
Mice, Knockout
Neurons
Gene knockdown
Mutation
fungi
Phenotype
Psychiatry and Mental health
030104 developmental biology
Knockout mouse
Neuroscience
Cell Adhesion Molecules
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14765578
- Volume :
- 26
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Molecular psychiatry
- Accession number :
- edsair.doi.dedup.....3ab2f96f84acd3fa0c5db927439d0f2b