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

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

Version 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

  • 9,489
    views
  • 1,303
    downloads
  • 147
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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
(2019)
Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs. isogenic control
eLife 8:e50333.
https://doi.org/10.7554/eLife.50333

Share this article

https://doi.org/10.7554/eLife.50333

Further reading

    1. Neuroscience
    Jack W Lindsey, Elias B Issa
    Research Article

    Object classification has been proposed as a principal objective of the primate ventral visual stream and has been used as an optimization target for deep neural network models (DNNs) of the visual system. However, visual brain areas represent many different types of information, and optimizing for classification of object identity alone does not constrain how other information may be encoded in visual representations. Information about different scene parameters may be discarded altogether (‘invariance’), represented in non-interfering subspaces of population activity (‘factorization’) or encoded in an entangled fashion. In this work, we provide evidence that factorization is a normative principle of biological visual representations. In the monkey ventral visual hierarchy, we found that factorization of object pose and background information from object identity increased in higher-level regions and strongly contributed to improving object identity decoding performance. We then conducted a large-scale analysis of factorization of individual scene parameters – lighting, background, camera viewpoint, and object pose – in a diverse library of DNN models of the visual system. Models which best matched neural, fMRI, and behavioral data from both monkeys and humans across 12 datasets tended to be those which factorized scene parameters most strongly. Notably, invariance to these parameters was not as consistently associated with matches to neural and behavioral data, suggesting that maintaining non-class information in factorized activity subspaces is often preferred to dropping it altogether. Thus, we propose that factorization of visual scene information is a widely used strategy in brains and DNN models thereof.

    1. Neuroscience
    Zhaoran Zhang, Huijun Wang ... Kunlin Wei
    Research Article

    The sensorimotor system can recalibrate itself without our conscious awareness, a type of procedural learning whose computational mechanism remains undefined. Recent findings on implicit motor adaptation, such as over-learning from small perturbations and fast saturation for increasing perturbation size, challenge existing theories based on sensory errors. We argue that perceptual error, arising from the optimal combination of movement-related cues, is the primary driver of implicit adaptation. Central to our theory is the increasing sensory uncertainty of visual cues with increasing perturbations, which was validated through perceptual psychophysics (Experiment 1). Our theory predicts the learning dynamics of implicit adaptation across a spectrum of perturbation sizes on a trial-by-trial basis (Experiment 2). It explains proprioception changes and their relation to visual perturbation (Experiment 3). By modulating visual uncertainty in perturbation, we induced unique adaptation responses in line with our model predictions (Experiment 4). Overall, our perceptual error framework outperforms existing models based on sensory errors, suggesting that perceptual error in locating one’s effector, supported by Bayesian cue integration, underpins the sensorimotor system’s implicit adaptation.