Functional neuronal defects in a human 3D cerebral cortical model of 22q11.2 deletion syndrome
Abstract/Contents
- Abstract
- 22q11.2 deletion syndrome (22q11DS) is a common genetic cause of developmental neuropsychiatric disorders, including psychosis and autism spectrum disorders. This highly penetrant syndrome provides a unique opportunity to identify specific neuronal phenotypes and to elucidate the mechanisms underlying neuropsychiatric disorders. Here, we generated induced pluripotent stem cells from a cohort of 15 subjects carrying the canonical deletion at the 22q11.2 locus and from 15 controls, and we differentiated these cells into three--dimensional organoids resembling the developing cerebral cortex. Transcriptional profiling across 100 days of in vitro developmental time showed high reliability of organoid differentiation and revealed changes in the expression of genes associated with neuronal excitability in 22q11DS. Using electrophysiological and live imaging methods, we identified defects in excitability and calcium signaling in organoid--derived cortical neurons, as well as in glutamatergic neurons differentiated in two--dimensional cultures. Interestingly, the calcium deficit was present over 5.5 months of maturation in vitro and was related to changes in the resting membrane potential that led to abnormal inactivation of voltage gated calcium channels. Importantly, heterozygous mutations in the 22q11.2 locus gene DGCR8 recapitulated the neuronal excitability and calcium phenotypes, and overexpression of this gene restored functional defects in cortical neurons. Moreover, the calcium abnormality in 22q11DS could also be acutely restored pharmacologically by application of several antipsychotic drugs. Taken together, our study reveals that a common chromosomal microdeletion disorder conferring a high risk for neuropsychiatric disease causes functional defects in developing human cortical neurons that may be related to loss of the DGCR8 gene.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Khan, Themasap Ahmad |
|---|---|
| Degree supervisor | Pasca, Sergiu |
| Thesis advisor | Pasca, Sergiu |
| Thesis advisor | Cui, Bianxiao |
| Thesis advisor | Palmer, Theo |
| Thesis advisor | Porteus, Matthew H |
| Degree committee member | Cui, Bianxiao |
| Degree committee member | Palmer, Theo |
| Degree committee member | Porteus, Matthew H |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Themasap Ahmad Khan. |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2020. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Themasap Ahmad Khan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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