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

oleh: 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

Format: Article
Diterbitkan: eLife Sciences Publications Ltd 2023-04-01

Deskripsi

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.