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Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

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Abstract

In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9−/− mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9−/− mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life.

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Acknowledgments

This work was supported by the Intramural Research Program of the NIH, NICHD and NINDS, and R01EY016431 to EMQ.

Compliance with Ethical Standards

The authors declare no potential conflicts of interest to disclose. All research involving animals conformed to the guidelines of the US Department of Health and Human Services and the University of Maryland and NIH Institutional Animal Care and Use Committees. This manuscript was submitted with the consent of all the authors.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    Sachiko Murase

  2. Department of Biology and Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD, 20742, USA

    Sachiko Murase, Crystal L. Lantz, Richard Higgins & Elizabeth M. Quinlan

  3. Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Eunyoung Kim & Dax A. Hoffman

  4. Laboratory of Cellular and Synaptic Neurophysiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Nitin Gupta & Mark Stopfer

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  1. Sachiko Murase
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Murase, S., Lantz, C.L., Kim, E. et al. Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability. Mol Neurobiol 53, 3477–3493 (2016). https://doi.org/10.1007/s12035-015-9295-y

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