1. Neuroscience
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Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs. isogenic control

  1. Swagata Ghatak
  2. Nima Dolatabadi
  3. Dorit Trudler
  4. XiaoTong Zhang
  5. Yin Wu
  6. Madhav Mohata
  7. Rajesh Ambasudhan
  8. Maria Talantova
  9. Stuart A Lipton  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. Scintillon Institute, United States
Research Article
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Cite this article as: eLife 2019;8:e50333 doi: 10.7554/eLife.50333

Abstract

Human Alzheimer's disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin 1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.

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Author details

  1. Swagata Ghatak

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nima Dolatabadi

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Dorit Trudler

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5835-3322
  4. XiaoTong Zhang

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yin Wu

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Madhav Mohata

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Rajesh Ambasudhan

    Neurodegenerative Disease Center, Scintillon Institute, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Maria Talantova

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Stuart A Lipton

    Neuroscience Translational Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, United States
    For correspondence
    slipton@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3490-1259

Funding

National Institutes of Health (P01 HD29587)

  • Stuart A Lipton

National Institute of Neurological Disorders and Stroke (Core grant P30 NS076411)

  • Stuart A Lipton

National Institutes of Health (DP1 DA041722)

  • Stuart A Lipton

National Institutes of Health (R01 NS086890)

  • Stuart A Lipton

National Institutes of Health (R01 AG056259)

  • Stuart A Lipton

National Institutes of Health (RF1 AG057409)

  • Stuart A Lipton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Publication history

  1. Received: July 18, 2019
  2. Accepted: November 21, 2019
  3. Accepted Manuscript published: November 29, 2019 (version 1)
  4. Version of Record published: December 11, 2019 (version 2)

Copyright

© 2019, Ghatak et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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