Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
Program in Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
Nat Med. 2020 Dec;26(12):1888-1898. doi: 10.1038/s41591-020-1043-9. Epub 2020 Sep 28.
22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.
22q11.2 缺失综合征（22q11DS）是一种高度外显且常见的神经精神疾病的遗传病因。在这里，我们从 15 名 22q11DS 患者和 15 名对照个体中生成了诱导多能干细胞，并将其分化为三维（3D）大脑皮质类器官。在 100 天的转录谱分析中，显示出分化的高度可靠性，并揭示了与神经元兴奋性相关基因的变化。通过电生理学和活体成像，我们在类器官和 2D 衍生的皮质神经元中鉴定出自发性神经元活动和钙信号的缺陷。钙缺乏与静息膜电位变化有关，导致电压门控钙通道的异常失活。DGCR8 的杂合缺失重现了兴奋性和钙表型，其过表达可挽救这些缺陷。此外，应用抗精神病药也可以恢复 22q11DS 的钙异常。总之，我们的研究说明了如何使用干细胞衍生模型来揭示和挽救与神经精神疾病的遗传形式相关的细胞表型。
