# 16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro

Article · Sundberg M, Pinson H, Smith RS, Winden KD, Venugopal P, Tai DJC, Gusella JF, Talkowski ME, Walsh CA, Tegmark M, Sahin M

- Archive id: doi:10.1038/s41467-021-23113-z
- Published: 2021-05-18
- Venue: Nature communications
- DOI: https://doi.org/10.1038/s41467-021-23113-z
- PMID: 34006844
- PMCID: PMC8131375
- Citations: 51
- Source URL: https://doi.org/10.1038/s41467-021-23113-z
- PDF: https://europepmc.org/articles/PMC8131375/pdf
- Provenance: europepmc

## Abstract

Reciprocal 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.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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