@article{62df6a66469d45e48131f639a1c8f43e,
title = "Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain",
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.",
keywords = "brain-derived neurotrophic factor, calcitonin gene-related peptide, chronic pain, colony-stimulating factor 1, high-frequency stimulation, long-term potentiation, microglia",
author = "Zhou, {Li Jun} and Jiyun Peng and Xu, {Ya Nan} and Zeng, {Wei Jie} and Jun Zhang and Xiao Wei and Mai, {Chun Lin} and Lin, {Zhen Jia} and Yong Liu and Madhuvika Murugan and Eyo, {Ukpong B.} and Umpierre, {Anthony D.} and Xin, {Wen Jun} and Tao Chen and Mingtao Li and Hui Wang and Richardson, {Jason R.} and Zhi Tan and Liu, {Xian Guo} and Wu, {Long Jun}",
note = "Funding Information: This work was supported by the National Institutes of Health , United States ( R21DE025689 and R01NS088627 ), the National Natural Science Foundation of China ( 81771204 , U1201223 , 8137119 , and 81270377 ), the Guangdong Province University Outstanding Young Teachers{\textquoteright} Training Program ( Yq2013008 ), and the Natural Science Foundation of Guangdong Province, China ( S2013010011889 and 2014A030313062 ). We thank Dr. Wen-Biao Gan (New York University) for providing CX3CR1 CreER/+ mice and Noriko Goldsmith (Rutgers University) for technical assistance with confocal microscopy. Also, we greatly appreciate all members of the Wu lab at Rutgers University and the Mayo Clinic for insightful discussions. Funding Information: This work was supported by the National Institutes of Health, United States (R21DE025689 and R01NS088627), the National Natural Science Foundation of China (81771204, U1201223, 8137119, and 81270377), the Guangdong Province University Outstanding Young Teachers{\textquoteright} Training Program (Yq2013008), and the Natural Science Foundation of Guangdong Province, China (S2013010011889 and 2014A030313062). We thank Dr. Wen-Biao Gan (New York University) for providing CX3CR1CreER/+ mice and Noriko Goldsmith (Rutgers University) for technical assistance with confocal microscopy. Also, we greatly appreciate all members of the Wu lab at Rutgers University and the Mayo Clinic for insightful discussions. L.-J.Z. J.R.R. Z.T. X.-G.L. and L.-J.W. conceived the study, designed the experiments, and wrote the manuscript. L.-J.Z. performed most of the experiments. J.P. and Y.-N.X. performed intrathecal injection of drugs and performed all blind pain behavior tests. L.-J.Z. Y.-N.X. W.-J.Z. and J.Z. performed the spinal culture, DRG neuron culture, and qRT-PCR experiments. W.-J.Z. Z.T. and T.C. performed the IEM experiments and data analysis. X.W. performed the experiment in rats. C.-L.M. Z.-J.L. Y.L. M.M. U.B.E. A.D.U. W.-J.X. M.L. and H.W. assisted with experiments. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = jun,
day = "25",
doi = "10.1016/j.celrep.2019.05.087",
language = "English (US)",
volume = "27",
pages = "3844--3859.e6",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}