Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain
Li-Jun Zhou,
Jiyun Peng,
Ya-Nan Xu,
Wei-Jie Zeng,
Jun Zhang,
Xiao Wei,
Chun-Lin Mai,
Zhen-Jia Lin,
Yong Liu,
Madhuvika Murugan,
Ukpong B. Eyo,
Anthony D. Umpierre,
Wen-Jun Xin,
Tao Chen,
Mingtao Li,
Hui Wang,
Jason R. Richardson,
Zhi Tan,
Xian-Guo Liu,
Long-Jun Wu
Affiliations
Li-Jun Zhou
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
Jiyun Peng
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Ya-Nan Xu
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Wei-Jie Zeng
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Jun Zhang
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Xiao Wei
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Chun-Lin Mai
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Zhen-Jia Lin
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Yong Liu
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Madhuvika Murugan
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Ukpong B. Eyo
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Anthony D. Umpierre
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Wen-Jun Xin
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
Tao Chen
Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Center, the Fourth Military Medical University, Xi’an 710032, China
Mingtao Li
Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
Hui Wang
Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA; Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 22600, China
Jason R. Richardson
Departments of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
Zhi Tan
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Corresponding author
Xian-Guo Liu
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China; Corresponding author
Long-Jun Wu
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA; Corresponding author
Summary: Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity. : Zhou et al. characterize chronic pain behaviors triggered by LTP-inducible HFS without nerve injury. They identify that HFS-induced LTP is accompanied by an increase in CGRP terminals in the spinal dorsal horn. Activation of neuronal CSF1-microglial BDNF signaling is indispensable for the synaptic and structural plasticity underlying HFS-induced chronic pain. Keywords: long-term potentiation, chronic pain, calcitonin gene-related peptide, microglia, high-frequency stimulation, colony-stimulating factor 1, brain-derived neurotrophic factor
