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

• Published in: Nature medicine Vol. 26; no. 12; pp. 1888 - 1898
• Main Authors: Khan, Themasap A., Revah, Omer, Gordon, Aaron, Yoon, Se-Jin, Krawisz, Anna K., Goold, Carleton, Sun, Yishan, Kim, Chul Hoon, Tian, Yuan, Li, Min-Yin, Schaepe, Julia M., Ikeda, Kazuya, Amin, Neal D., Sakai, Noriaki, Yazawa, Masayuki, Kushan, Leila, Nishino, Seiji, Porteus, Matthew H., Rapoport, Judith L., Bernstein, Jonathan A., O’Hara, Ruth, Bearden, Carrie E., Hallmayer, Joachim F., Huguenard, John R., Geschwind, Daniel H., Dolmetsch, Ricardo E., Paşca, Sergiu P.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2020; Nature Publishing Group
• Subjects: 631/378/1689; 631/532/1360; Adult; Antipsychotics; Biomedical and Life Sciences; Biomedicine; Calcium; Calcium channels; Calcium channels (voltage-gated); Calcium Signaling - genetics; Calcium signalling; Cancer Research; Cell culture; Cell Differentiation - genetics; Cerebral Cortex - pathology; Cerebral Cortex - ultrastructure; Complications and side effects; Defects; Deletion; Development and progression; DiGeorge syndrome; DiGeorge Syndrome - diagnosis; DiGeorge Syndrome - pathology; Electrophysiology; Excitability; Female; Genetic aspects; Humans; Inactivation; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - ultrastructure; Infectious Diseases; Male; Membrane potential; Mental disorders; Mental illness; Metabolic Diseases; Molecular Medicine; Neurons - pathology; Neurons - ultrastructure; Neurosciences; Organoids; Organoids - pathology; Organoids - ultrastructure; Phenotypes; Pluripotency; Risk factors; Stem cells; Transcription; Young Adult; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-020-1043-9

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.