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Cover  Neurotransmitter release from neurons occurs by fusion of synaptic vesicles (SVs) with the presynaptic plasma membrane of the axon terminal. For many years now, the subsequent recycling pathways of SV membrane proteins and their local reincorporation into newly formed SVs have been subject of intense study. One of the first papers that morphologically characterized this pathway was by Heuser and Reese (J. Cell Biol. [1973]. 57, 315-344). In this often-cited paper, morphological changes in stimulated frog neuromuscular junctions were described that revealed some critical important features of SV recycling. First, by quantitative measurements of membrane lengths, it was shown that stimulation resulted in a redistribution of SV membranes to the plasma membrane. The events following exocytosis were followed by activating cells in the presence of the extracellular added tracer horseradish peroxidase (HRP). The authors showed that initial uptake was primarily mediated by coated vesicles, the nature of which now is known to be clathrin. Shortly after stimulation, the formation of irregularly formed membrane cisternae was observed that contained HRP but were not connected to the cell surface (Figure 25, 2 min after stimulation). Only after prolonged incubation with HRP was the tracer detected in SVs, whereas the number of HRP-loaded cisternae was largely reduced (Figure 28, 1 h after stimulation). These data suggested that SVs reform from endosome-like intermediates, a notion that has proven to be an important basis for our current understanding of SV recycling.Judith Klumperman.