Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs

Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the <i>SHANK3</i> gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a <i>Shank3</i> mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte (OL) features, similar to its role in neurons. This was shown by impaired molecular and physiological glutamatergic traits of InsG3680-derived primary OL cultures. In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination-related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell-derived OLs from a patient with the InsG3680 mutation. Together, our study provides insight into Shank3's role in OLs and reveals a mechanism of the crucial connection of myelination to ASD pathology.

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Publication Details

Journal
Science Advances
Published
2024-10-11
DOI
https://doi.org/10.1126/sciadv.adl4573
Citations
20
Primary Topic
Autism Spectrum Disorder Research
Type
article
Field-Weighted Citation Impact
6.85
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article

Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs

Boaz Barak, Avi Schroeder, Galit Elad‐Sfadia, Gal Chen et al.
20 citations
Science Advances
Autism Spectrum Disorder Research
6.85
article

Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs

Boaz Barak, Avi Schroeder, Galit Elad‐Sfadia, Gal Chen, Sophie Shohat, Idan Rosh, Inbar Fischer, Utkarsh Tripathi, Yara Hussein, Patrícia Monteiro, Ben M. Maoz, Shani Stern, Ritu Nayak, Yaniv Assaf, Yael Leichtmann‐Bardoogo, Ela Bar, May Rokach, Aviram Shemen, Ana Carolina Castro, Sari Schokoroy-Trangle, Adi Soffer, G. Wiener
article en
20 citations

Abstract

Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the <i>SHANK3</i> gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a <i>Shank3</i> mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte (OL) features, similar to its role in neurons. This was shown by impaired molecular and physiological glutamatergic traits of InsG3680-derived primary OL cultures. In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination-related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell-derived OLs from a patient with the InsG3680 mutation. Together, our study provides insight into Shank3's role in OLs and reveals a mechanism of the crucial connection of myelination to ASD pathology.

Science AdvancesVol. 10(41)
Tel Aviv University (IL), Technion – Israel Institute of Technology (IL), Universidade do Porto (PT), University of Haifa (IL)
Quality Education
Openalex Percentile: Top 2%
Autism Spectrum Disorder Research
6.85
DOIOpen Access PDFOpenAlex
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