Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
27
11
2019
accepted:
30
07
2020
pubmed:
30
9
2020
medline:
29
1
2021
entrez:
29
9
2020
Statut:
ppublish
Résumé
22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.
Identifiants
pubmed: 32989314
doi: 10.1038/s41591-020-1043-9
pii: 10.1038/s41591-020-1043-9
pmc: PMC8525897
mid: NIHMS1726998
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1888-1898Subventions
Organisme : NIMH NIH HHS
ID : R01 MH094714
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH121075
Pays : United States
Organisme : NIMH NIH HHS
ID : R37 MH060233
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH107800
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH115746
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH100900
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH115745
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH085953
Pays : United States
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