Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles

  1. Sayali V Gore
  2. Eric J James
  3. Lin-Chien Huang
  4. Jenn J Park
  5. Andrea Berghella
  6. Adrian Thompson
  7. Hollis T Cline
  8. Carlos Aizenman  Is a corresponding author
  1. Brown University, United States
  2. The Scripps Research Institute, United States

Abstract

Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 may also lead to neurodevelopmental disorders (ND). Here we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed in Xenopus tadpoles after early exposure to valproic acid (VPA), a known teratogen associated with ND in humans. In Xenopus tadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development.

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. Sayali V Gore

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Eric J James

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lin-Chien Huang

    The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jenn J Park

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrea Berghella

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Adrian Thompson

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hollis T Cline

    The Dorris Neuroscience Center, 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:" 0000-0002-4887-9603
  8. Carlos Aizenman

    Department of Neuroscience, Brown University, Providence, United States
    For correspondence
    carlos_aizenman@brown.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7378-7217

Funding

National Science Foundation (GRFP)

  • Eric J James

National Eye Institute (R01 EY027380)

  • Carlos Aizenman

Brown University (Carney New Frontiers and OVPR SEED award)

  • Carlos Aizenman

National Eye Institute (R01 EY011261)

  • Lin-Chien Huang
  • Hollis T Cline

National Institute of Neurological Disorders and Stroke (NS076006)

  • Lin-Chien Huang
  • Hollis T Cline

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

Ethics

Animal experimentation: All animal experiments were performed in accordance with and approved by Brown University Institutional Animal Care and Use Committee standards and guidelines (Protocol number 19-05-0016).

Reviewing Editor

  1. Lisa M Monteggia, Vanderbilt University, United States

Publication history

  1. Preprint posted: May 31, 2020 (view preprint)
  2. Received: August 15, 2020
  3. Accepted: July 18, 2021
  4. Accepted Manuscript published: July 20, 2021 (version 1)
  5. Accepted Manuscript updated: July 23, 2021 (version 2)
  6. Version of Record published: July 27, 2021 (version 3)

Copyright

© 2021, Gore 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. Sayali V Gore
  2. Eric J James
  3. Lin-Chien Huang
  4. Jenn J Park
  5. Andrea Berghella
  6. Adrian Thompson
  7. Hollis T Cline
  8. Carlos Aizenman
(2021)
Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles
eLife 10:e62147.
https://doi.org/10.7554/eLife.62147
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