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

Author

Listed:
  • Maria Sundberg

    (Harvard Medical School)

  • Hannah Pinson

    (MIT
    Vrije Universiteit Brussel)

  • Richard S. Smith

    (Harvard Medical School)

  • Kellen D. Winden

    (Harvard Medical School)

  • Pooja Venugopal

    (Harvard Medical School)

  • Derek J. C. Tai

    (Massachusetts General Hospital
    Harvard Medical School)

  • James F. Gusella

    (Massachusetts General Hospital
    Harvard Medical School
    Harvard University
    Program in Medical and Population Genetics Broad Institute of MIT and Harvard)

  • Michael E. Talkowski

    (Massachusetts General Hospital
    Program in Medical and Population Genetics Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Christopher A. Walsh

    (Harvard Medical School)

  • Max Tegmark

    (MIT)

  • Mustafa Sahin

    (Harvard Medical School)

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.

Suggested Citation

  • 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 & Mustafa Sahin, 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, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23113-z
    DOI: 10.1038/s41467-021-23113-z
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    Cited by:

    1. Lauren Rylaarsdam & Jennifer Rakotomamonjy & Eleanor Pope & Alicia Guemez-Gamboa, 2024. "iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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