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).

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.

Metrics

  • 1,743
    views
  • 179
    downloads
  • 13
    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. 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

Share this article

https://doi.org/10.7554/eLife.62147

Further reading

    1. Neuroscience
    Christopher Bell, Lukas Kilo ... Stefanie Ryglewski
    Research Article

    At many vertebrate synapses, presynaptic functions are tuned by expression of different Cav2 channels. Most invertebrate genomes contain only one Cav2 gene. The Drosophila Cav2 homolog, cacophony (cac), induces synaptic vesicle release at presynaptic active zones (AZs). We hypothesize that Drosophila cac functional diversity is enhanced by two mutually exclusive exon pairs that are not conserved in vertebrates, one in the voltage sensor and one in the loop binding Caβ and Gβγ subunits. We find that alternative splicing in the voltage sensor affects channel activation voltage. Only the isoform with the higher activation voltage localizes to AZs at the glutamatergic Drosophila larval neuromuscular junction and is imperative for normal synapse function. By contrast, alternative splicing at the other alternative exon pair tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other reduces channel number in the AZ and thus release probability. This also abolishes presynaptic homeostatic plasticity. Moreover, reduced channel number affects short-term plasticity, which is rescued by increasing the external calcium concentration to match release probability to control. In sum, in Drosophila alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Cav2 gene.

    1. Neuroscience
    Hans Auer, Donna Gift Cabalo ... Jessica Royer
    Research Article

    The amygdala is a subcortical region in the mesiotemporal lobe that plays a key role in emotional and sensory functions. Conventional neuroimaging experiments treat this structure as a single, uniform entity, but there is ample histological evidence for subregional heterogeneity in microstructure and function. The current study characterized subregional structure-function coupling in the human amygdala, integrating post-mortem histology and in vivo MRI at ultra-high fields. Core to our work was a novel neuroinformatics approach that leveraged multiscale texture analysis as well as non-linear dimensionality reduction techniques to identify salient dimensions of microstructural variation in a 3D post-mortem histological reconstruction of the human amygdala. We observed two axes of subregional variation in this region, describing inferior-superior as well as mediolateral trends in microstructural differentiation that in part recapitulated established atlases of amygdala subnuclei. Translating our approach to in vivo MRI data acquired at 7 Tesla, we could demonstrate the generalizability of these spatial trends across 10 healthy adults. We then cross-referenced microstructural axes with functional blood-oxygen-level dependent (BOLD) signal analysis obtained during task-free conditions, and revealed a close association of structural axes with macroscale functional network embedding, notably the temporo-limbic, default mode, and sensory-motor networks. Our novel multiscale approach consolidates descriptions of amygdala anatomy and function obtained from histological and in vivo imaging techniques.