1. Neuroscience

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

  1. Xin-Tai Wang
  2. Lin Zhou
  3. Bin-Bin Dong
  4. Fang-Xiao Xu
  5. De-Juan Wang
  6. En-Wei Shen
  7. Xin-Yu Cai
  8. Yin Wang
  9. Na Wang
  10. Sheng-Jian Ji
  11. Wei Chen
  12. Martijn Schonewille
  13. J Julius Zhu  Is a corresponding author
  14. Chris I De Zeeuw  Is a corresponding author
  15. Ying Shen  Is a corresponding author
  1. Zhejiang University, China
  2. Ningxia Medical University, China
  3. Southern University of Science and Technology, China
  4. Erasmus MC, Netherlands
  5. University of Virginia, United States
https://doi.org/10.7554/eLife.80875
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Cite this article
  1. Xin-Tai Wang
  2. Lin Zhou
  3. Bin-Bin Dong
  4. Fang-Xiao Xu
  5. De-Juan Wang
  6. En-Wei Shen
  7. Xin-Yu Cai
  8. Yin Wang
  9. Na Wang
  10. Sheng-Jian Ji
  11. Wei Chen
  12. Martijn Schonewille
  13. J Julius Zhu
  14. Chris I De Zeeuw
  15. Ying Shen
(2023)
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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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

  1. Xin-Tai Wang

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Lin Zhou

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Bin-Bin Dong

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Fang-Xiao Xu

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  5. De-Juan Wang

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  6. En-Wei Shen

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Xin-Yu Cai

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Yin Wang

    Department of Physiology, Ningxia Medical University, Yinchuan, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Na Wang

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1438-1508

  10. Sheng-Jian Ji

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3380-258X

  11. Wei Chen

    Department of Physiology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  12. Martijn Schonewille

    Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2675-1393

  13. J Julius Zhu

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    For correspondence
    jjzhu@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1879-983X

  14. Chris I De Zeeuw

    Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands
    For correspondence
    c.dezeeuw@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5628-8187

  15. Ying Shen

    Department of Physiology, Zhejiang University, Hangzhou, China
    For correspondence
    yshen@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7034-5328

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.

Ethics

Animal experimentation: All of the animals were handled according to approved protocol of the Animal Experimentation Ethics Committee of Zhejiang University (ZJU17067).

Reviewing Editor

  1. Jun Ding, Stanford University, United States

Version history

  1. Received: June 7, 2022
  2. Preprint posted: June 17, 2022 (view preprint)
  3. Accepted: April 25, 2023
  4. Accepted Manuscript published: April 26, 2023 (version 1)
  5. 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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  1. Xin-Tai Wang
  2. Lin Zhou
  3. Bin-Bin Dong
  4. Fang-Xiao Xu
  5. De-Juan Wang
  6. En-Wei Shen
  7. Xin-Yu Cai
  8. Yin Wang
  9. Na Wang
  10. Sheng-Jian Ji
  11. Wei Chen
  12. Martijn Schonewille
  13. J Julius Zhu
  14. Chris I De Zeeuw
  15. Ying Shen
(2023)
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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