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University of Massachusetts Amherst

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Nat. Commun., 2023 Jun 24;14(1):3770 | https://doi.org/10.1038/s41467-023-39420-6 Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids

Rebecca Sebastian ^1,2,8, Kang Jin ^3,4,8, Narciso Pavon ², Ruby Bansal ²,Andrew Potter³, Yoonjae Song ², Juliana Babu ², Rafael Gabriel ², Yubing Sun ⁵, Bruce Aronow ^3,4,6,7 & ChangHui Pak ^2,*

¹Graduate Program in Neuroscience & Behavior, UMass Amherst, Amherst, MA 01003, USA.
²Department of Biochemistry and Molecular Biology, UMass Amherst, Amherst, MA 01003, USA.
³Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
⁴Department of Biomedical Informatics, University of Cincinnati, Cincinnati, OH 45229, USA.
⁵Department of Mechanical and Industrial Engineering, UMass Amherst, Amherst, MA 01003, USA.
⁶Department of Electrical Engineering and Computer Science, University of Cincinnati, Cincinnati, OH 45221, USA.
⁷Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45256, USA.
⁸These authors contributed equally: Rebecca Sebastian, Kang Jin.

*Corresponding author: correspondence to ChangHui Pak

Abstract

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.

논문정보

형식Research article
게재일2023년 06월 (BRIC 등록일 2023-06-27)
연구진국외 연구진
분야 생명과학 > 세포생물학

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