Parallel processing of quickly and slowly mobilized reserve vesicles in hippocampal synapses

Quickly and slowly mobilized reserve vesicles within presynaptic terminals are thought to be contained within separate pools that are connected in series. However, here we use FM-dyes to show that the two types are mobilized in parallel, without intermixing. The result supports a re-conceptualization of synaptic vesicle trafficking, proposed previously, where: (1) active zones contain multiple independent docking/release sites; (2) the release sites vary in probability of catalyzing exocytosis following individual action potentials; and (3), each docked vesicle is connected to a separate reserve. The re-conceptualization is then supported further by evidence that alterations in the timing of reserve pool depletion in synapsin knockouts are largest during lightest use even though alterations in short-term synaptic plasticity are largest during heavy use. The re-conceptualization implies that low release probability sites account for both reluctant readily releasable vesicles and slowly mobilized reserves. Extensive heterogeneity suggests that synapses have the capacity to store information by modulating the ratio of low to high probability release sites.