title: TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.
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.
  
  
  
  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.affiliation: 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.
authors.forename: Yong
authors.identifier: 0000-0003-1278-7114
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zhou
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jun
authors.identifier: 0000-0001-7246-0522
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Li
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Ren
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.|Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors.forename: Jiyun
authors.identifier: 0000-0002-9912-8930
authors.initials: J
authors.lastname: Peng
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wei
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Wen-Jun
authors.identifier: 0000-0002-5380-8738
authors.initials: WJ
authors.lastname: Xin
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Beijing, 100101 China.
authors.forename: Zhi-Hai
authors.initials: ZH
authors.lastname: Qin
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.|Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors.forename: Madhuvika
authors.identifier: 0000-0002-0706-0730
authors.initials: M
authors.lastname: Murugan
authors.affiliation: 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.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: 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.
authors.forename: Long-Jun
authors.identifier: 0000-0001-8019-3380
authors.initials: LJ
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D014409:Tumor Necrosis Factor-alpha
keywords: SNI; TNF-α; memory deficit; microglia; neuropathic pain; synaptic plasticity