16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro
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s41467-021-23113-z.pdf
Description
Published version
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7.7 MB
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Checksum (MD5)
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Author(s)
Sundberg, Maria
Pinson, Hannah
Smith, Richard S
Winden, Kellen D
Venugopal, Pooja
Tai, Derek JC
Gusella, James F
Talkowski, Michael E
Walsh, Christopher A
Tegmark, Max
Date Issued
2021
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Sundberg, Maria, Pinson, Hannah, Smith, Richard S, Winden, Kellen D, Venugopal, Pooja et al. 2021. "16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro." Nature Communications, 12 (1).
Version
Final published version
Abstract
AbstractReciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.
MIT Department
Massachusetts Institute of Technology. Department of Physics
Center for Brains, Minds, and Machines
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1038/S41467-021-23113-Z
