美国斯坦福大学Sergiu P. Paca团队取得新进展。他们发现22q11.2缺失综合征（22q11DS）人类细胞模型的神经元缺陷。相关论文发表在2020年9月28日出版的《自然-医学》杂志上。

他们从15名22q11DS个体和15名对照个体中分离出诱导性多能干细胞，并将它们分化为三维（3D）脑皮质类器官。跨越100天的转录图谱显示了分化的高度可靠性，并揭示了神经元兴奋性相关基因的变化。使用电生理学和实时成像，他们在类器官和2D来源的皮质神经元中发现了自发性神经元活动和钙信号传导的缺陷。

钙缺乏与静息膜电位变化有关，从而导致电压门控钙通道异常失活。DGCR8杂合性丢失概括了兴奋性和钙表型，其过表达挽救了这些缺陷。此外，也可通过应用抗精神病药来恢复22q11DS钙异常。

综上所述，我们他们的研究说明了如何使用干细胞来源的模型来发现和挽救与神经精神疾病的遗传形式相关的细胞表型。

研究人员表示，22q11DS是神经精神疾病的高度渗透性和常见遗传因素。

附：英文原文

Title: Neuronal defects in a human cellular model of 22q11.2 deletion syndrome

Author: Themasap A. Khan, Omer Revah, Aaron Gordon, Se-Jin Yoon, Anna K. Krawisz, Carleton Goold, Yishan Sun, Chul Hoon Kim, Yuan Tian, Min-Yin Li, Julia M. Schaepe, Kazuya Ikeda, Neal D. Amin, Noriaki Sakai, Masayuki Yazawa, Leila Kushan, Seiji Nishino, Matthew H. Porteus, Judith L. Rapoport, Jonathan A. Bernstein, Ruth OHara, Carrie E. Bearden, Joachim F. Hallmayer, John R. Huguenard, Daniel H. Geschwind, Ricardo E. Dolmetsch, Sergiu P. Paca

Issue&Volume: 2020-09-28

Abstract: 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. A human stem cell–derived model helps to uncover neuronal phenotypes associated with genetic forms of neuropsychiatric disease.

DOI: 10.1038/s41591-020-1043-9

Source: https://www.nature.com/articles/s41591-020-1043-9