%0 Journal Article
%T cAMP-EPAC-PKCε-RIM1α signaling regulates presynaptic long-term potentiation and motor learning.
%A Wang XT
%A Zhou L
%A Dong BB
%A Xu FX
%A Wang DJ
%A Shen EW
%A Cai XY
%A Wang Y
%A Wang N
%A Ji SJ
%A Chen W
%A Schonewille M
%A Zhu JJ
%A De Zeeuw CI
%A Shen Y
%J Elife
%V 12
%N 0
%D 2023 04 26
%M 37159499
%F 8.713
%R 10.7554/eLife.80875
%X The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here, we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior in mice. Presynaptic cAMP-EPAC-PKCε signaling cascade induces a previously unidentified threonine phosphorylation of RIM1α, and thereby initiates the assembly of the Rab3A-RIM1α-Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC-PKCε 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.