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

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 O'Hara; Carrie E Bearden; Joachim F Hallmayer; John R Huguenard; Daniel H Geschwind; Ricardo E Dolmetsch; Sergiu P Paşca

doi:10.1038/s41591-020-1043-9

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

Nat Med. 2020 Dec;26(12):1888-1898. doi: 10.1038/s41591-020-1043-9. Epub 2020 Sep 28.

Authors

Themasap A Khan^#^{1

2}, Omer Revah^#¹, Aaron Gordon^#³, Se-Jin Yoon¹, Anna K Krawisz^{4

5}, Carleton Goold⁴, Yishan Sun⁴, Chul Hoon Kim^{4

6}, Yuan Tian^{3

7}, Min-Yin Li¹, Julia M Schaepe¹, Kazuya Ikeda⁸, Neal D Amin¹, Noriaki Sakai¹, Masayuki Yazawa^{4

9}, Leila Kushan¹⁰, Seiji Nishino¹, Matthew H Porteus⁸, Judith L Rapoport¹¹, Jonathan A Bernstein⁸, Ruth O'Hara¹, Carrie E Bearden^{10

12

13}, Joachim F Hallmayer¹, John R Huguenard¹⁴, Daniel H Geschwind^{3

15

16

17}, Ricardo E Dolmetsch¹⁸, Sergiu P Paşca^{19

20}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
² Program in Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
³ Program in Neurogenetics, Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Neurobiology, Stanford University, Stanford, CA, USA.
⁵ Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁶ Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁷ Interdepartmental PhD Program in Bioinformatics, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Pediatrics, Stanford University, Stanford, CA, USA.
⁹ Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁰ Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
¹¹ National Institute of Mental Health, Child Psychiatry Branch, Bethesda, MD, USA.
¹² Department of Psychology, University of California Los Angeles, Los Angeles, CA, USA.
¹³ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
¹⁵ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁶ Center for Autism Research and Treatment, Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
¹⁷ Institute of Precision Health, University of California Los Angeles, Los Angeles, CA, USA.
¹⁸ Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
¹⁹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. spasca@stanford.edu.
²⁰ Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. spasca@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Calcium Signaling / genetics*
Cell Differentiation / genetics
Cerebral Cortex / pathology
Cerebral Cortex / ultrastructure*
DiGeorge Syndrome / diagnosis*
DiGeorge Syndrome / pathology
Female
Humans
Induced Pluripotent Stem Cells / metabolism
Induced Pluripotent Stem Cells / ultrastructure
Male
Neurons / pathology
Neurons / ultrastructure*
Organoids / pathology
Organoids / ultrastructure
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding