Tags

Type your tag names separated by a space and hit enter

TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.
J Neurosci. 2017 01 25; 37(4):871-881.JN

Abstract

Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits.

SIGNIFICANCE STATEMENT

Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn (SDH) but inhibits LTP in hippocampus. The opposite changes in synaptic plasticity may contribute to chronic pain and memory deficits, respectively. However, the structural and molecular bases of these alterations of synaptic plasticity are unclear. Here, we show that the complexity of excitatory synaptic connectivity and brain-derived neurotrophic factor (BDNF) expression are enhanced in SDH but reduced in the hippocampus in neuropathic pain and the opposite changes depend on tumor necrosis factor-alpha/tumor necrosis factor receptor 1 signaling and microglial activation. The region-dependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury.

Authors+Show Affiliations

Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854. Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, and.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China. Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 510080 China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.National Laboratory of Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Beijing, 100101 China.Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854. Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, and.Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, liuxg@mail.sysu.edu.cn lwu@dls.rutgers.edu. Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, and.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, liuxg@mail.sysu.edu.cn lwu@dls.rutgers.edu. Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 510080 China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28123022

Citation

Liu, Yong, et al. "TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord By Microglia-Dependent Mechanisms After Peripheral Nerve Injury." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 37, no. 4, 2017, pp. 871-881.
Liu Y, Zhou LJ, Wang J, et al. TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. J Neurosci. 2017;37(4):871-881.
Liu, Y., Zhou, L. J., Wang, J., Li, D., Ren, W. J., Peng, J., Wei, X., Xu, T., Xin, W. J., Pang, R. P., Li, Y. Y., Qin, Z. H., Murugan, M., Mattson, M. P., Wu, L. J., & Liu, X. G. (2017). TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 37(4), 871-881. https://doi.org/10.1523/JNEUROSCI.2235-16.2016
Liu Y, et al. TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord By Microglia-Dependent Mechanisms After Peripheral Nerve Injury. J Neurosci. 2017 01 25;37(4):871-881. PubMed PMID: 28123022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. AU - Liu,Yong, AU - Zhou,Li-Jun, AU - Wang,Jun, AU - Li,Dai, AU - Ren,Wen-Jie, AU - Peng,Jiyun, AU - Wei,Xiao, AU - Xu,Ting, AU - Xin,Wen-Jun, AU - Pang,Rui-Ping, AU - Li,Yong-Yong, AU - Qin,Zhi-Hai, AU - Murugan,Madhuvika, AU - Mattson,Mark P, AU - Wu,Long-Jun, AU - Liu,Xian-Guo, PY - 2016/07/13/received PY - 2016/11/18/revised PY - 2016/12/02/accepted PY - 2017/1/27/entrez PY - 2017/1/27/pubmed PY - 2017/8/2/medline KW - SNI KW - TNF-α KW - memory deficit KW - microglia KW - neuropathic pain KW - synaptic plasticity SP - 871 EP - 881 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 37 IS - 4 N2 - : Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits. SIGNIFICANCE STATEMENT: Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn (SDH) but inhibits LTP in hippocampus. The opposite changes in synaptic plasticity may contribute to chronic pain and memory deficits, respectively. However, the structural and molecular bases of these alterations of synaptic plasticity are unclear. Here, we show that the complexity of excitatory synaptic connectivity and brain-derived neurotrophic factor (BDNF) expression are enhanced in SDH but reduced in the hippocampus in neuropathic pain and the opposite changes depend on tumor necrosis factor-alpha/tumor necrosis factor receptor 1 signaling and microglial activation. The region-dependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/28123022/TNF_α_Differentially_Regulates_Synaptic_Plasticity_in_the_Hippocampus_and_Spinal_Cord_by_Microglia_Dependent_Mechanisms_after_Peripheral_Nerve_Injury_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=28123022 DB - PRIME DP - Unbound Medicine ER -