Restoration of Cingulate Long-Term Depression by Enhancing Non-apoptotic Caspase 3 Alleviates Peripheral Pain Hypersensitivity

Yong-Jie Wang; Ming-Gang Liu; Jing-Hua Wang; Wei Cao; Cheng Wu; Zi-Yue Wang; Li Liu; Fan Yang; Zhi-Hui Feng; Li Sun; Fuxing Zhang; Yi Shen; Yu-Dong Zhou; Min Zhuo; Jian-Hong Luo; Tian-Le Xu; Xiang-Yao Li

doi:10.1016/j.celrep.2020.108369

Restoration of Cingulate Long-Term Depression by Enhancing Non-apoptotic Caspase 3 Alleviates Peripheral Pain Hypersensitivity

Cell Rep. 2020 Nov 10;33(6):108369. doi: 10.1016/j.celrep.2020.108369.

Authors

Yong-Jie Wang¹, Ming-Gang Liu², Jing-Hua Wang³, Wei Cao³, Cheng Wu³, Zi-Yue Wang³, Li Liu⁴, Fan Yang⁵, Zhi-Hui Feng⁶, Li Sun³, Fuxing Zhang⁷, Yi Shen³, Yu-Dong Zhou³, Min Zhuo⁸, Jian-Hong Luo⁹, Tian-Le Xu¹⁰, Xiang-Yao Li¹¹

Affiliations

¹ Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China; Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, and The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
² Collaborative Innovation Centre for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China.
⁴ Core Facilities of the School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
⁵ Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China.
⁶ Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, and The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
⁷ Department of Anatomy and K. K. Leung Brain Research Center, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
⁸ Center for Neuron and Disease, Frontier Institutes of Life Science, Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁹ Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China. Electronic address: luojianhong@zju.edu.cn.
¹⁰ Collaborative Innovation Centre for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xu-happiness@shsmu.edu.cn.
¹¹ Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China. Electronic address: lixiangy@zju.edu.cn.

PMID: 33176141
DOI: 10.1016/j.celrep.2020.108369

Abstract

Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of ∼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management.

Keywords: Casp3 and GluA1 interaction; GluA1 internalization; GluA2; LTD; caspase 3; hypersensitivity; neuropathic pain; non-apoptotic function; spontaneous pain; synaptic transmission.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Caspase 3 / metabolism*
Depression / genetics*
Gyrus Cinguli / physiopathology*
Humans
Neuralgia / physiopathology*

Substances

Caspase 3