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cAMP-EPAC-PKCε-RIM1α signaling regulates presynaptic long-term potentiation and motor learning

Onderzoeksgroep De Zeeuw
Publicatiejaar 2023
Gepubliceerd in eLife
Auteur(s) Xin-Tai Wang, Lin Zhou, Bin-Bin Dong, Fang-Xiao Xu, De-Juan Wang, En-Wei Shen, Xin-Yu Cai, Yin Wang, Na Wang, Sheng-Jian Ji, Wei Chen, Martijn Schonewille, J Julius Zhu, Chris I De Zeeuw, Ying Shen

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.

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