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.
De novo mutations and copy number variations (CNVs) in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). How NRXN1 CNVs impact cortical development in a cell type-specific manner and how disease genetic background modulates these phenotypes are unclear. Here, we leveraged human pluripotent stem cell-derived brain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single cell transcriptomic analysis over the course of cortical brain organoid development from 3 weeks to 3.5 months. We identified maturing glutamatergic and GABAergic neurons as being consistently impacted due to NRXN1 CNVs irrespective of genetic background, contributed in part by altered gene modules in ubiquitin-mediated pathways, splicing, and synaptic signaling. Moreover, while isogenic NRXN1 CNVs impact differentiation and maturation of neurons and astroglia, cell composition and developmental trajectories of early neural progenitors are affected in SCZ-NRXN1 CNVs. Our study reveals developmental timing dependent NRXN1 CNV-induced cellular mechanisms in SCZ at single cell resolution and highlights the emergence of disease-specific transcriptomic signatures and cellular vulnerabilities, which can arise from interaction between genetic variants and disease background.
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