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    The extracellular matrix (ECM) is crucial for brain development, regulating dynamic synapses. ECM remodeling by microglial MMP14 and brevican maintains synapse stability and plasticity during development.

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    Area of Science:

    • Neuroscience
    • Developmental Biology
    • Cell Biology

    Background:

    • Synaptic plasticity is vital for brain development and function.
    • The extracellular matrix (ECM) influences synaptic plasticity, but its developmental role is poorly understood.
    • Existing research primarily focuses on adult synaptic plasticity mechanisms.

    Purpose of the Study:

    • To investigate the role of ECM remodeling in maintaining dynamic neuronal synapses during brain development.
    • To define the mechanisms by which ECM components regulate synapse stability and density.
    • To explore the involvement of microglial matrix metalloproteinase 14 (MMP14) and brevican in synaptic plasticity.

    Main Methods:

    • Live imaging of excitatory synapses in zebrafish hindbrain.
    • Genetic manipulation (brevican deletion, MMP14 knockout).
    • Enzymatic digestion of the ECM.
    • Human induced pluripotent stem cell (iPSC)-derived neuronal cultures.
    • Motor learning behavioral assays.
    • Mathematical modeling.

    Main Results:

    • Observed a bimodal distribution of dynamic (short-lived) and stable (longer-lived) synapses.
    • ECM disruption destabilized dynamic synapses, reducing overall synapse density.
    • Loss of microglial MMP14 led to brevican accumulation and an expanded stable synapse pool, increasing synapse density.
    • MMP14 and brevican were essential for experience-dependent synaptic plasticity in a motor learning task.

    Conclusions:

    • ECM remodeling is essential for maintaining a dynamic subset of synapses during brain development.
    • Microglial MMP14 plays a critical role in regulating ECM composition and synaptic stability.
    • Brevican acts as a key ECM component influencing synapse dynamics and plasticity.