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Here, we report that the EPAC-PKC\u03b5 module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior in mice. Presynaptic cAMP\u2212EPAC\u2212PKC\u03b5 signaling cascade induces a previously unidentified threonine phosphorylation of RIM1\u03b1, and thereby initiates the assembly of the Rab3A\u2212RIM1\u03b1\u2212Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC\u2212PKC\u03b5 signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms.<\/jats:p>","DOI":"10.7554\/elife.80875","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T08:00:23Z","timestamp":1682496023000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.80875","source":"Crossref","is-referenced-by-count":11,"title":["cAMP\u2212EPAC\u2212PKC\u03b5\u2212RIM1\u03b1 signaling regulates presynaptic long-term potentiation and motor learning"],"prefix":"10.7554","volume":"12","author":[{"given":"Xin-Tai","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00a2xv884","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, 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