cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning
- Zhejiang University, China
- Ningxia Medical University, China
- Southern University of Science and Technology, China
- Erasmus MC, Netherlands
- University of Virginia, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1, 2, and Figure 1-figure supplement 2, 3, and 4.
Article and author information
Author details
Martijn Schonewille
Funding
National Innovation of Science and Technology-2030 (2021ZD0204000)
- Ying Shen
Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20160331115633182)
- Sheng-Jian Ji
Science and Technology Programme of Hangzhou Municipality (20190101A10)
- Wei Chen
Key Realm R&D Program of Guangdong Province (2019B030335001)
- Wei Chen
Ningxia Key Research and Development Program (2021BEG03097)
- Yin Wang
Natural Science Foundation of Zhejiang Province (LQ17C090001)
- Na Wang
ERC-Stg (680235)
- Martijn Schonewille
Dutch Organization for Medical Sciences
- Chris I De Zeeuw
Dutch Organization for Life Sciences
- Chris I De Zeeuw
ERC-adv and ERC-POC of the EU
- Chris I De Zeeuw
INTENSE
- Chris I De Zeeuw
National Natural Science Foundation of China (81625006)
- Ying Shen
NIN Vriendenfonds for albinism
- Chris I De Zeeuw
National Natural Science Foundation of China (31820103005)
- Ying Shen
National Natural Science Foundation of China (32000692)
- Xin-Tai Wang
National Natural Science Foundation of China (32160192)
- Yin Wang
National Natural Science Foundation of China (32100791)
- Fang-Xiao Xu
National Natural Science Foundation of China (31900741)
- Lin Zhou
National Natural Science Foundation of China (32170976)
- Lin Zhou
National Key Research and Development Program of China (2020YFB1313500)
- Lin Zhou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jun Ding, Stanford University, United States
Ethics
Animal experimentation: All of the animals were handled according to approved protocol of the Animal Experimentation Ethics Committee of Zhejiang University (ZJU17067).
Version history
- Received: June 7, 2022
- Preprint posted: June 17, 2022 (view preprint)
- Accepted: April 25, 2023
- Accepted Manuscript published: April 26, 2023 (version 1)
- Version of Record published: May 10, 2023 (version 2)
Copyright
© 2023, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning
eLife 12:e80875.
https://doi.org/10.7554/eLife.80875
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