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Here, using electron- and super-resolution microscopy at the Drosophila neuromuscular junction we quantitatively map vesicle:Ca2+ channel coupling distances. These are very heterogeneous, resulting in a broad spectrum of vesicular release probabilities within synapses. Stochastic simulations of transmitter release from vesicles placed according to this distribution revealed strong constraints on short-term plasticity; particularly facilitation was difficult to achieve. We show that postulated facilitation mechanisms operating via activity-dependent changes of vesicular release probability (e.g. by a facilitation fusion sensor) generate too little facilitation and too much variance. In contrast, Ca2+-dependent mechanisms rapidly increasing the number of releasable vesicles reliably reproduce short-term plasticity and variance of synaptic responses. We propose activity-dependent inhibition of vesicle un-priming or release site activation as novel facilitation mechanisms.<\/jats:p>","DOI":"10.7554\/elife.51032","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T08:00:25Z","timestamp":1582185625000},"source":"Crossref","is-referenced-by-count":62,"title":["Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0313-6205","authenticated-orcid":true,"given":"Janus RL","family":"Kobbersmed","sequence":"first","affiliation":[{"name":"Department of Mathematical Sciences, University of Copenhagen, K\u00f8benhavn, Denmark"},{"name":"Department of Neuroscience, University of Copenhagen, K\u00f8benhavn, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5895-6529","authenticated-orcid":true,"given":"Andreas 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