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

Author:

Wang Xin-Tai12,Zhou Lin1,Dong Bin-Bin1,Xu Fang-Xiao1,Wang De-Juan1,Shen En-Wei1,Cai Xin-Yu1,Wang Yin3,Wang Na1ORCID,Ji Sheng-Jian4ORCID,Chen Wei1,Schonewille Martijn5ORCID,Zhu J Julius6ORCID,De Zeeuw Chris I57ORCID,Shen Ying189ORCID

Affiliation:

1. Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine

2. Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University

3. Key Laboratory of Cranial Cerebral Diseases, Department of Neurobiology of Basic Medical College, Ningxia Medical University

4. Department of Biology, Southern University of Science and Technology

5. Department of Neuroscience, Erasmus MC

6. Department of Pharmacology, University of Virginia

7. Netherlands Institute for Neuroscience, Royal Academy of Sciences

8. International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine

9. Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine

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.

Funder

National Innovation of Science and Technology-2030

National Natural Science Foundation of China

National Key Research and Development Program of China

Science, Technology and Innovation Commission of Shenzhen Municipality

Science and Technology Programme of Hangzhou Municipality

Key Realm R&D Program of Guangdong Province

Ningxia Key Research and Development Program

Natural Science Foundation of Zhejiang Province

ERC-Stg

Dutch Organization for Medical Sciences

Dutch Organization for Life Sciences

ERC-adv and ERC-POC of the EU

INTENSE

NIN Vriendenfonds for albinism

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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