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
Affiliations
Xin-Tai Wang
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
Lin Zhou
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Bin-Bin Dong
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Fang-Xiao Xu
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
De-Juan Wang
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
En-Wei Shen
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Xin-Yu Cai
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Yin Wang
Key Laboratory of Cranial Cerebral Diseases, Department of Neurobiology of Basic Medical College, Ningxia Medical University, Yinchuan, China
Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands; Netherlands Institute for Neuroscience, Royal Academy of Sciences, Amsterdam, Netherlands
Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China; Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
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.
