Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

• Published in: Cell Reports
• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2019-06-01
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719307260

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