1. Neuroscience
Download icon

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
  • Cited 21
  • Views 4,559
  • Annotations
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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

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.

Metrics

  • 4,559
    Page views
  • 705
    Downloads
  • 21
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    2. Neuroscience
    Laura Morcom et al.
    Research Article Updated

    The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

    1. Neuroscience
    Maria Rita Karlocai et al.
    Research Article Updated

    The molecular mechanisms underlying the diversity of cortical glutamatergic synapses are still incompletely understood. Here, we tested the hypothesis that presynaptic active zones (AZs) are constructed from molecularly uniform, independent release sites (RSs), the number of which scales linearly with the AZ size. Paired recordings between hippocampal CA1 pyramidal cells and fast-spiking interneurons in acute slices from adult mice followed by quantal analysis demonstrate large variability in the number of RSs (N) at these connections. High-resolution molecular analysis of functionally characterized synapses reveals variability in the content of one of the key vesicle priming factors – Munc13-1 – in AZs that possess the same N. Replica immunolabeling also shows a threefold variability in the total Munc13-1 content of AZs of identical size and a fourfold variability in the size and density of Munc13-1 clusters within the AZs. Our results provide evidence for quantitative molecular heterogeneity of RSs and support a model in which the AZ is built up from variable numbers of molecularly heterogeneous, but independent RSs.