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

Maria Sundberg, Hannah Pinson, Richard S. Smith, Kellen D. Winden, Pooja Venugopal, Derek J. C. Tai, James F. Gusella, Michael E. Talkowski, Christopher A. Walsh, Max Tegmark and Mustafa Sahin ()
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Maria Sundberg: Harvard Medical School
Hannah Pinson: MIT
Richard S. Smith: Harvard Medical School
Kellen D. Winden: Harvard Medical School
Pooja Venugopal: Harvard Medical School
Derek J. C. Tai: Massachusetts General Hospital
James F. Gusella: Massachusetts General Hospital
Michael E. Talkowski: Massachusetts General Hospital
Christopher A. Walsh: Harvard Medical School
Max Tegmark: MIT
Mustafa Sahin: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23113-z

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