Modes of vesicle retrieval at ribbon synapses, calyx-type synapses, and small central synapses.

Introduction Endocytosis is essential for the maintenance of synaptic transmission because it recycles and thus prevents complete depletion of synaptic vesicles in the nerve terminal. The goal of understanding synaptic vesicle recycling mechanisms was launched in earnest in 1973 when John Heuser and Tom Reese published their landmark electron microscope images of synaptic terminals of the frog neuromuscular junction (NMJ) (Heuser and Reese, 1973) back-to-back with those of the group of Bruno Ceccarelli (Cec-carelli et al., 1973). Soon after these publications, however, a debate arose regarding this issue, which was summed up by John Heuser in a later review article (Heuser, 1989a): " Two schools of thought have developed, one holding that vesicles acquire tracers directly via a reversible exo/endocytotic sequence in which they consistently maintain their biochemical identity during their transient continuity with the plasma membrane, the other holding that synaptic vesicles acquire tracers indirectly, via the formation of clathrin-coated vesicles which are spatially and temporally separate from exocytosis and reverse a temporary loss of the ves-icles' individual identity upon merger with the plasma membrane. " In total, at least three forms of endocytosis have been hypothesized to operate at synapses (Fig. 1). As indicated above, in the best characterized form, a full collapse of vesicle occurs with the plasma membrane during exocytosis, followed by clathrin-mediated invagination and fission during endocytosis (Heuser and Reese, 1973; Heuser, 1989b). This form is called full collapse fusion and retrieval. " Kiss-and-run " exocytosis and en-docytosis involves fusion followed rapidly by fission without full collapse of vesicle membrane (Ceccarelli et al., 1973; Fesce et al., 1994). The original tracer experiments of Heuser and Reese also revealed that, after heavy stimulation, an endosome-like intracel-lular structure transiently appears, from which vesicles bud off (Heuser and Reese, 1973). Endosome-like structures are likely the result of bulk endocytosis, retrieval of a large piece of membrane directly from the plasma membrane (Koenig and Ikeda,