The vesicular hypothesis originally introduced to explain the quantal nature of presynaptic neurotransmitter (NT) release has been initially confirmed by the presence of NT within presynaptic vesicles and by an exo-endocytotic traffic associated with intense synaptic activity. Since then, an increasing number of synaptic transmission properties cannot be readily incorporated into the now popular model in which each quantal NT packet is prepared in a vesicle and is released by diffusion across the synaptic cleft when this vesicle fuses transiently or definitively with the plasma membrane. Interestingly, presynaptic exocytosis exhibits the characteristics of the ubiquitous secretory pathway by which all eukaryotic cells interact with their immediate environment, not just externalizing soluble products, but principally delivering at particular location of the cell surface specific glycoconjugates constituting the extracellular matrix (ECM) that mediates intercellular adhesion, recognition and signaling. Recent studies point to the involvement of vesicular glycoproteins in fast transmission after their incorporation into the transsynaptic ECM, or synaptomatrix. The notion of synaptomatrix is presented as a multimolecular tight arrangement that is dynamically remodeled in a use-dependent fashion via PKC to support synaptic morpho-functional plasticity. The data reviewed suggests that the synaptomatrix controls in a Ca(2+) entry-dependent manner the solubility of the NT in the cleft to support fast transmission.
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