Exocytosis at synapses involves fusion between vesicles and the plasma membrane1. Although compound fusion between vesicles2,3 was proposed to occur at ribbon-type synapses4,5, whether it exists, how it is mediated, and what role it plays at conventional synapses remain unclear. Here we report the existence of compound fusion, its underlying mechanism, and its role at a nerve terminal containing conventional active zones in rats and mice. We found that high potassium application and high frequency firing induced giant capacitance up-steps, reflecting exocytosis of vesicles larger than regular ones, followed by giant down-steps, reflecting bulk endocytosis. These intense stimuli also induced giant vesicle-like structures, as observed with electron microscopy, and giant miniature excitatory postsynaptic currents (mEPSCs), reflecting more transmitter release. Calcium and its sensor for vesicle fusion, synaptotagmin, were required for these giant events. After high frequency firing, calcium/synaptotagmin-dependent mEPSC size increase was paralleled by calcium/synaptotagmin-dependent post-tetanic potentiation. These results suggest a new route of exocytosis and endocytosis composed of three steps. First, calcium/synaptotagmin mediates compound fusion between vesicles. Second, exocytosis of compound vesicles increases quantal size, which increases synaptic strength and contributes to the generation of post-tetanic potentiation. Third, exocytosed compound vesicles are retrieved via bulk endocytosis. We suggest that this vesicle cycling route be included in models of synapses in which only vesicle fusion with the plasma membrane is considered1.
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We thank J. Diamond and K. Paradiso for comments on the manuscript, and S. Cheng, R. Azzam and V. Crocker for help in EM. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program (L.-G.W.) and the American Heart Association (R.A.).
Author Contributions L.H. performed cell-attached recordings; L.X. performed EM work, and the mEPSC and EPSC recordings; J.X. and B.D.M. helped with some experiments; L.B. helped with EM work and maintained Syt2-/- mice; E.M. and R.A. generated the Syt2-/- mouse line; and L.-G.W. supervised the project and wrote the paper.
This file contains Supplementary Notes, Supplementary Results, Supplementary Methods, Supplementary Figures S1-S8 with Legends and Supplementary References
About this article
Nature Neuroscience (2012)