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

被引：105

作者：

Khan, Themasap A. ^{[1
,2
]}

Revah, Omer ^{[1
]}

Gordon, Aaron ^{[3
]}

Yoon, Se-Jin ^{[1
]}

Krawisz, Anna K. ^{[4
,18
]}

Goold, Carleton ^{[4
]}

Sun, Yishan ^{[4
]}

Kim, Chul Hoon ^{[4
,5
]}

Tian, Yuan ^{[3
,6
]}

Li, Min-Yin ^{[1
]}

Schaepe, Julia M. ^{[1
]}

Ikeda, Kazuya ^{[7
]}

Amin, Neal D. ^{[1
]}

Sakai, Noriaki ^{[1
]}

Yazawa, Masayuki ^{[4
,19
]}

Kushan, Leila ^{[8
]}

Nishino, Seiji ^{[1
]}

Porteus, Matthew H. ^{[7
]}

Rapoport, Judith L. ^{[9
]}

Bernstein, Jonathan A. ^{[7
]}

O'Hara, Ruth ^{[1
]}

Bearden, Carrie E. ^{[8
,10
,11
]}

Hallmayer, Joachim F. ^{[1
]}

Huguenard, John R. ^{[12
]}

Geschwind, Daniel H. ^{[3
,13
,14
,15
]}

Dolmetsch, Ricardo E. ^{[16
]}

Pasca, Sergiu P. ^{[1
,17
]}

机构：

[1] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA

[2] Stanford Univ, Program Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[3] Univ Calif Los Angeles, Dept Neurol, Program Neurogenet, Los Angeles, CA USA

[4] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA

[5] Yonsei Univ, Dept Pharmacol, Coll Med, Seoul, South Korea

[6] Univ Calif Los Angeles, Interdept PhD Program Bioinformat, Los Angeles, CA USA

[7] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[8] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA

[9] Natl Inst Mental Hlth, Child Psychiat Branch, Bethesda, MD USA

[10] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA

[11] Univ Calif Los Angeles, Semel Inst Neurosci, Ctr Neurobehav Genet, Human Behav, Los Angeles, CA USA

[12] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[13] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA USA

[14] Univ Calif Los Angeles, Semel Inst, Ctr Autism Res & Treatment, Los Angeles, CA USA

[15] Univ Calif Los Angeles, Inst Precis Hlth, Los Angeles, CA USA

[16] Novartis Inst BioMed Res, Cambridge, MA USA

[17] Stanford Univ, Wu Tsai Neurosci Inst, Stanford Brain Organogenesis Program, Stanford, CA 94305 USA

[18] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiol, Boston, MA USA

[19] Columbia Univ, Vagelos Coll Phys & Surg, Dept Mol Pharmacol & Therapeut, Columbia Stem Cell Initiat,Dept Rehabil & Regener, New York, NY USA

来源：

NATURE MEDICINE | 2020年 / 26卷 / 12期

基金：

美国国家科学基金会; 美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

PSYCHIATRIC-DISORDERS; ANTIPSYCHOTIC-DRUGS; RECEPTOR MODULATION; MOUSE MODEL; HIGH-RATES; EXPRESSION; SCHIZOPHRENIA; EXCITABILITY; BRAIN; STEM;

D O I：

10.1038/s41591-020-1043-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A human stem cell-derived model helps to uncover neuronal phenotypes associated with genetic forms of neuropsychiatric disease. 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 ofDGCR8recapitulated 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.

引用

页码：1888 / 1898

页数：33

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