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, LongJun Wu

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3844-3859.e6
JournalCell reports
Volume27
Issue number13
DOIs
StatePublished - Jun 25 2019

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Keywords

  • brain-derived neurotrophic factor
  • calcitonin gene-related peptide
  • chronic pain
  • colony-stimulating factor 1
  • high-frequency stimulation
  • long-term potentiation
  • microglia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhou, L. J., Peng, J., Xu, Y. N., Zeng, W. J., Zhang, J., Wei, X., Mai, C. L., Lin, Z. J., Liu, Y., Murugan, M., Eyo, U. B., Umpierre, A. D., Xin, W. J., Chen, T., Li, M., Wang, H., Richardson, J. R., Tan, Z., Liu, X. G., & Wu, L. (2019). Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain. Cell reports, 27(13), 3844-3859.e6. https://doi.org/10.1016/j.celrep.2019.05.087