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Compound vesicle fusion increases quantal size and potentiates synaptic transmission

2009; Nature Portfolio; Volume: 459; Issue: 7243 Linguagem: Inglês

10.1038/nature07860

1476-4687

Liming He, Lei Xue, Jianhua Xu, Benjamin D. McNeil, Li Bai, Ernestina Melicoff, Roberto Adachi, Ling-Gang Wu,

Neuroscience and Neuropharmacology Research

Synaptic transmission is believed to function on a quantal mode, that is: through the fusion of one synaptic vesicle with the plasma membrane at a time. New work from Ling-Gang Wu's group at the National Institute of Neurological Disorders and Stroke now describes the fusion of synaptic vesicles with themselves, prior to the release of giant vesicles at a central synapse. The work implicates calcium-dependent synaptotagmin-2 in a mechanism that may apply to previously described compound vesicle fusion in non-neuronal, endocrine cells and at some more peripheral synapses. The study indicates that compound fusion is a significant contributor to synaptic potentiation, with implications for neuronal plasticity and disorders such as epilepsy. Synaptic transmission is believed to function through the fusion of one synaptic vesicle with the plasma membrane at a time, but here the fusion of synaptic vesicles with themselves before release of giant vesicles at a central synapse is described. 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.