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

• Published in: Cell reports (Cambridge) Vol. 27; no. 13; pp. 3844 - 3859.e6
• Main Authors: Zhou, Li-Jun, Peng, Jiyun, Xu, Ya-Nan, Zeng, Wei-Jie, Zhang, Jun, Wei, Xiao, Mai, Chun-Lin, Lin, Zhen-Jia, Liu, Yong, Murugan, Madhuvika, Eyo, Ukpong B., Umpierre, Anthony D., Xin, Wen-Jun, Chen, Tao, Li, Mingtao, Wang, Hui, Richardson, Jason R., Tan, Zhi, Liu, Xian-Guo, Wu, Long-Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.06.2019; Elsevier
• Subjects: Animals; brain-derived neurotrophic factor; calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - genetics; Calcitonin Gene-Related Peptide - metabolism; chronic pain; Chronic Pain - genetics; Chronic Pain - metabolism; Chronic Pain - pathology; colony-stimulating factor 1; high-frequency stimulation; Long-Term Potentiation; Mice; Mice, Transgenic; microglia; Microglia - metabolism; Microglia - pathology; Neuronal Plasticity; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Spinal Cord Dorsal Horn - metabolism; Spinal Cord Dorsal Horn - pathology; chronic pain; colony-stimulating factor 1; calcitonin gene-related peptide; brain-derived neurotrophic factor; microglia; high-frequency stimulation; long-term potentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.05.087

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. [Display omitted] •HFS triggers synaptic plasticity of CGRP afferents and chronic pain•LTP-inducible HFS activates spinal microglia through CSF1 signaling•Microglial BDNF is essential for HFS-induced spinal LTP and chronic pain 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.