TY - JOUR
T1 - Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs
AU - Fischer, Inbar
AU - Shohat, Sophie
AU - Leichtmann-Bardoogo, Yael
AU - Nayak, Ritu
AU - Wiener, Gal
AU - Rosh, Idan
AU - Shemen, Aviram
AU - Tripathi, Utkarsh
AU - Rokach, May
AU - Bar, Ela
AU - Hussein, Yara
AU - Castro, Ana Carolina
AU - Chen, Gal
AU - Soffer, Adi
AU - Schokoroy-Trangle, Sari
AU - Elad-Sfadia, Galit
AU - Assaf, Yaniv
AU - Schroeder, Avi
AU - Monteiro, Patricia
AU - Stern, Shani
AU - Maoz, Ben M.
AU - Barak, Boaz
N1 - Publisher Copyright:
Copyright © 2024 The Authors,
PY - 2024/10/11
Y1 - 2024/10/11
N2 - Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the SHANK3 gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a Shank3 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.
AB - Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the SHANK3 gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a Shank3 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.
UR - http://www.scopus.com/inward/record.url?scp=85206122944&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adl4573
DO - 10.1126/sciadv.adl4573
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C2 - 39392881
AN - SCOPUS:85206122944
SN - 2375-2548
VL - 10
JO - Science advances
JF - Science advances
IS - 41
M1 - eadl4573
ER -
