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Related Experiment Video

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Extracellular matrix proteolysis maintains synapse plasticity during brain development.

Haruna Nakajo1, Ran Cao1, Supriya A Mula1

  • 1Department of Psychiatry and Behavioral Sciences/Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

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|December 22, 2025
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The extracellular matrix (ECM) maintains dynamic synapses crucial for brain development and motor learning. Microglial MMP14 and brevican are key regulators of synapse stability and plasticity.

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • The extracellular matrix (ECM) influences synaptic plasticity, but its developmental roles are not fully understood.
  • Previous studies primarily focused on ECM functions in adult brains.

Purpose of the Study:

  • To investigate the role of ECM remodeling in regulating synapse dynamics and plasticity during brain development.
  • To define the specific contributions of brevican and matrix metalloproteinase 14 (MMP14) to synapse stability.

Main Methods:

  • Live imaging of excitatory synapses in zebrafish hindbrain.
  • Genetic manipulation (brevican deletion, MMP14 loss) and ECM digestion.
  • Analysis of synapse density, lifetime, and experience-dependent plasticity.
  • Utilized human induced pluripotent stem cell-derived cultures and mathematical modeling.

Main Results:

  • Synapses exhibit a bimodal distribution of dynamic and stable populations.
  • ECM disruption destabilized dynamic synapses, reducing overall synapse density.
  • Loss of microglial MMP14 increased brevican levels, prolonging dynamic synapse lifespan and increasing density.
  • MMP14 and brevican were essential for experience-dependent motor learning.

Conclusions:

  • ECM remodeling is critical for maintaining a dynamic subset of synapses during development.
  • Microglial MMP14 and brevican play essential, coordinated roles in regulating synapse stability and plasticity.
  • These findings provide new insights into the molecular mechanisms governing brain development and synaptic function.