Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer's circuit dysfunction

Abstract

Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Here we show that entorhinal cortex layer 2 (EC2) neurons are unusually vulnerable to prolonged neuronal inactivity compared with neighboring regions of the temporal lobe, and that reelin+ stellate cells connecting EC with the hippocampus are preferentially susceptible within the EC2 population. We demonstrate that neuronal death after silencing can be elicited through multiple independent means of activity inhibition, and that preventing synaptic release, either alone or in combination with electrical shunting, is sufficient to elicit silencing-induced degeneration. Finally, we discovered that degeneration following synaptic silencing is governed by competition between active and inactive cells, which is a circuit refinement process traditionally thought to end early in postnatal life. Our data suggests that the developmental window for wholesale circuit plasticity may extend into adulthood for specific brain regions. We speculate that this sustained potential for remodeling by entorhinal neurons may support lifelong memory but renders them vulnerable to prolonged activity changes in disease.

Data availability

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

Article and author information

Author details

  1. Rong Zhao

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Stacy D Grunke

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Caleb A Wood

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Gabriella A Perez

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Melissa Comstock

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ming-Hua Li

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Anand K Singh

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kyung-Won Park

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Joanna L Jankowsky

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    jankowsk@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5593-2310

Funding

National Institute on Aging (RF1 AG058188)

  • Joanna L Jankowsky

National Institute on Aging (RF1 AG058188-01S1)

  • Joanna L Jankowsky

National Institute on Aging (R01 NS092615)

  • Joanna L Jankowsky

Howard Hughes Medical Institute (GT13620)

  • Joanna L Jankowsky

National Institute on Aging (F31 AG067676)

  • Caleb A Wood

Alzheimer's Association (AARF-17-533487)

  • Stacy D Grunke

BrightFocus Foundation (A2015016F)

  • Stacy D Grunke

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

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Ethics

Animal experimentation: Animals were handled and housed in accordance with recommendations in the NIH Guide for Care and Use of Laboratory Animals. All animal procedures were reviewed and approved by the BCM IACUC under protocol AN-4975.

Version history

  1. Preprint posted: October 19, 2021 (view preprint)
  2. Received: September 29, 2022
  3. Accepted: December 3, 2022
  4. Accepted Manuscript published: December 5, 2022 (version 1)
  5. Version of Record published: January 24, 2023 (version 2)

Copyright

© 2022, Zhao 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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  1. Rong Zhao
  2. Stacy D Grunke
  3. Caleb A Wood
  4. Gabriella A Perez
  5. Melissa Comstock
  6. Ming-Hua Li
  7. Anand K Singh
  8. Kyung-Won Park
  9. Joanna L Jankowsky
(2022)
Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer's circuit dysfunction
eLife 11:e83813.
https://doi.org/10.7554/eLife.83813

Share this article

https://doi.org/10.7554/eLife.83813

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