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Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cel...
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Published in: | Nature communications 2023-06, Vol.14 (1), p.3770-3770, Article 3770 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | De novo mutations and copy number deletions in
NRXN1
(2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how
NRXN1
deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying
NRXN1
heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-
NRXN1
deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of
NRXN1
deletions in unique genetic contexts.
Copy number deletions in 2p16.3 locus (NRXN1) in individuals significantly increase risk for schizophrenia. Here, authors show, at single cell level, genetic background-specific effects that culminate in synaptic dysfunction using iPSC-derived brain organoid model. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-023-39420-6 |