Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles
- Brown University, United States
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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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.
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).
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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Role of matrix metalloproteinase-9 in neurodevelopmental disorders and plasticity in Xenopus tadpoles
eLife 10:e62147.
https://doi.org/10.7554/eLife.62147
