Molecular Mechanisms in Synaptic Vesicle Endocytosis and Recycling

process. The number of clathrin-coated vesicles and endosome-like structures generally increase in the pe-Department of Cell Biology Howard Hughes Medical Institute riod of recovery after stimulation (Heuser and Reese, 1973). Both clathrin and clathrin accessory proteins are Yale University School of Medicine New Haven, Connecticut 06510 highly concentrated in nerve terminals, and synaptic vesicle proteins represent the main cargo of brain Neurons exchange information at synapses with topo-clathrin-coated vesicles (Maycox et al., 1992). Dynamin plays an essential role in synaptic vesicle reformation logical precision and speed by capitalizing on the general property of all cells to recycle vesicles at the cell (Koenig and Ikeda, 1989), and the evidence discussed below demonstrates that clathrin and dynamin play periphery. " Fast " neurotransmitters are stored in synap-tic vesicles that release their content into the synaptic complementary functions in endocytosis. In fact, as with the proteins involved in exocytosis, clathrin coats were cleft by exocytosis. The selective clustering and docking of these vesicles at the presynaptic plasmalemma en-first characterized in brain tissue because neurons are highly specialized for the recycling of synaptic vesicles. sures spatial specificity, and the short delay between nerve terminal depolarization and their exocytosis en-Despite this evidence, a precise correlation between rate of exocytosis and number of either clathrin-coated sures speed. After fusion, synaptic vesicle membranes are rapidly recycled by endocytosis and reused for the vesicles or endosomal structures is not always observed. An alternative mechanism of synaptic vesicle generation of new synaptic vesicles. Given the relationship of this vesicle recycling pathway to the housekeep-reformation involving rapid closure of a transient exocy-totic fusion pore—the " kiss and run " hypothesis—was ing recycling pathway used by all cells, elucidation of the mechanisms of synaptic vesicle reformation broad-proposed to occur in parallel with the clathrin-mediated pathway and to predominate under moderate conditions ens our knowledge of the general mechanisms of exo-cytosis–endocytosis. of stimulation (Fesce et al., 1994). This model has recently gained support from studies on the effects of the protein kinase inhibitor staurosporine on synaptic Time Course of Recycling vesicle recycling. Stimulation of nerve terminals in the The recent development of endocytic probes to label presence of staurosporine produces release of neuro-synaptic vesicles membranes in living neurons (Kras-transmitters but not of preinternalized FM1-43, consis-zewski et al., 1995; Betz and Wu, 1995) has helped tent with the formation of a transient exocytotic opening greatly in defining the dynamics of synaptic vesicle recy-that …