Journal
NATURE MEDICINE
Volume 26, Issue 12, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-020-1043-9
Keywords
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Funding
- US National Institutes of Health (NIH) BRAINS Award [MH107800]
- NARSAD Young Investigator Award (Behavioral and Brain Foundation)
- MQ Fellow Award
- NYSCF Robertson Stem Cell Investigator Award
- CZI Ben Barres Investigator Award
- Stanford Human Brain Organogenesis Program
- Brain Rejuvenation Project
- Uytengsu Research Funds
- Kwan Research Fund
- California Institute of Regenerative Medicine (CIRM)
- NIH [R01MH100900, R01MH100900-S1]
- NIMH [R01 MH085953, R01 MH085953-08:S1, 5R37 MH060233, 5R01 MH094714]
- National Research Foundation of Korea grant [NRF-2019R1A2C3002354]
- Lucile Packard Foundation for Children's Health
- National Institute of Mental Health
- Stanford Graduate Fellowship (SGF)
- National Science Foundation (NSF) Fellowship
- Stanford Dean's Fellowship
- Feldman Gift Fund
- Maternal and Child Health Research Institute (MCHRI) Fellowship
- Autism Science Foundation (ASF)
- Brain and Behavior Research Foundation (BBRF) Young Investigator award
- HHMI Fellowship
- Stanford Bio-X Undergraduate Fellowship
- DGIST RAMP
- D Program of the Korean Ministry of Science and ICT AMP
- Future Planning [14-BD-16]
- National Research Foundation of Korea [4199990714142] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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