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Single cell transcriptomic profiling of human brain organoids reveals developmental timing- and cell-type-specific vulnerabilities induced by NRXN1 CNVs in schizophrenia

ABSTRACT: De novomutations and copy number variations (CNVs) inNRXN1(2p16.3) pose a significant risk for schizophrenia (SCZ). HowNRXN1CNVs 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 carryingNRXN1heterozygous 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 toNRXN1CNVs irrespective of genetic background, contributed in part by altered gene modules in ubiquitin-mediated pathways, splicing, and synaptic signaling. Moreover, while isogenicNRXN1CNVs impact differentiation and maturation of neurons and astroglia, cell composition and developmental trajectories of early neural progenitors are affected in SCZ-NRXN1CNVs. Our study reveals developmental timing dependentNRXN1CNV-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228315 | GEO | 2023/03/27

REPOSITORIES: GEO

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Project description:Induced pluripotent stem cell (iPSC) technology presents a unique opportunity to model schizophrenia (SCZ) and other neuropsychiatric disorders in vitro by providing investigators with the means to grow patient-specific neurons. Three approaches are possible regarding disease modeling for a genetically heterogenous disorder, like SCZ. One is the draw subjects from the general patient population who have suspected but undefined disease-causing genetic variants. Another is to focus on a common phenotype, such as clinical presentation, response to medications or age of onset. The third is to use patients who have on a common genetic etiology. We have chosen the latter approach and are developing a library of iPSCs from patients with SCZ who harbor chromosome 22q11.2 microdeletions. In this preliminary study involving 4 patients and 4 controls, gene expression profiling was carried out on early differentiating neurons using RNA-seq. Several important observations were made. First, despite the dramatic molecular changes that occur during the reprogramming of a somatic cell into an iPSC, and its subsequent differentiation into neurons, processes that require months of cultivation with multiple changes in growth medium and treatment with a variety of growth factors, we show that 22q11.2 haploinsufficiency at the DNA level is recapitulated in vitro by substantial decreases in the expression of nearly every gene in the deleted region. Overall, transcriptome profiling revealed significant changes in the expression of 604 genes (423 increased in the SCZ samples, 181 decreased; >1.5-fold change, uncorrected p<0.05). Among the differentially expressed genes were a number of SCZ candidates and genes involved in retinoic acid (RA) signaling. In addition, there was some overlap with the differentially expressed genes found in another study using SCZ patients who do not have 22q11.2 del, one of which was CYP26A1, which codes for one of the major enzymes involved in RA metabolism. Although the sample size in this preliminary study is small, the findings support the idea that dysregulated RA-signaling could be a potential target for therapeutic intervention in SZ associated with 22q11.2 del, and perhaps other subgroups of patients. 4 controls and 4 patients

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Single cell transcriptomic profiling of human brain organoids reveals developmental timing- and cell-type-specific vulnerabilities induced by NRXN1 CNVs in schizophrenia

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