Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles
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
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.
Reviewing Editor
- Lisa M Monteggia, Vanderbilt University, United States
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).
Version history
- Preprint posted: May 31, 2020 (view preprint)
- Received: August 15, 2020
- Accepted: July 18, 2021
- Accepted Manuscript published: July 20, 2021 (version 1)
- Accepted Manuscript updated: July 23, 2021 (version 2)
- 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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