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Accumulating data support the importance of interactions between pre- and postsynaptic neuronal elements with astroglial processes and extracellular matrix (ECM) for formation and plasticity of chemical synapses, and thus validate the concept of a tetrapartite synapse. Here we outline the major mechanisms driving: (i) synaptogenesis by secreted extracellular scaffolding molecules, like thrombospondins (TSPs), neuronal pentraxins (NPs) and cerebellins, which respectively promote presynaptic, postsynaptic differentiation or both; (ii) maturation of synapses via reelin and integrin ligands-mediated signaling; and (iii) regulation of synaptic plasticity by ECM-dependent control of induction and consolidation of new synaptic configurations. Particularly, we focused on potential importance of activity-dependent concerted activation of multiple extracellular proteases, such as ADAMTS4/5/15, MMP9 and neurotrypsin, for permissive and instructive events in synaptic remodeling through localized degradation of perisynaptic ECM and generation of proteolytic fragments as inducers of synaptic plasticity.

Shaping Synapses by the Neural Extracellular Matrix