1. National Institute of Neurological Disorders and Stroke, 35 Convent Drive, Building 35, Room 2B-1012, Bethesda, Maryland 20892, USA
2. Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, 2121 West Holcombe Boulevard, Box 1100, Houston, Texas 77030, USA
3. These authors contributed equally to this work.

Correspondence to: Ling-Gang Wu¹ Correspondence and requests for materials should be addressed to L.-G.W. (Email: wul@ninds.nih.gov).

Abstract

Exocytosis at synapses involves fusion between vesicles and the plasma membrane¹. Although compound fusion between vesicles^{2, 3} was proposed to occur at ribbon-type synapses^{4, 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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