前脑
诱导多能干细胞
精神分裂症(面向对象编程)
生物
神经科学
神经节隆起
转录组
表型
神经发育障碍
心理学
加巴能
胚胎干细胞
基因表达
基因
遗传学
精神科
中枢神经系统
抑制性突触后电位
作者
Tomoyo Sawada,André R. Barbosa,Bruno Henrique Silva Araújo,Alejandra E. McCord,Laura D’Ignazio,Kynon J.M. Benjamin,Bonna Sheehan,Michael Zabolocki,Arthur Feltrin,Raman Arora,Anna C. Brandtjen,Joel E. Kleinman,Thomas M. Hyde,Cédric Bardy,Daniel R. Weinberger,Apuã C.M. Paquola,Jennifer A. Erwin
标识
DOI:10.1176/appi.ajp.20220723
摘要
Objective: Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs). Methods: VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs). Results: Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort. Conclusions: The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.
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