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

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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

8 Citations (Scopus)
43 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere80875
JournaleLife
Volume12
DOIs
Publication statusPublished - 26 Apr 2023

Keywords

  • Animals
  • Mice
  • Cerebellum/physiology
  • Long-Term Potentiation/physiology
  • Neurons
  • Purkinje Cells
  • Synapses/physiology
  • Guanine Nucleotide Exchange Factors

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