TNF-α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury

Yong Liu, Li Jun Zhou, Jun Wang, Dai Li, Wen Jie Ren, Jiyun Peng, Xiao Wei, Ting Xu, Wen Jun Xin, Rui Ping Pang, Yong Yong Li, Zhi Hai Qin, Madhuvika Murugan, Mark P. Mattson, Long-Jun Wu, Xian Guo Liu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)871-881
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number4
DOIs
StatePublished - Jan 25 2017

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Peripheral Nerve Injuries
Neuronal Plasticity
Microglia
Hippocampus
Spinal Cord
Tumor Necrosis Factor-alpha
Memory Disorders
Neuralgia
Wounds and Injuries
Long-Term Potentiation
Brain-Derived Neurotrophic Factor
Chronic Pain
Neurons
Unmyelinated Nerve Fibers
Pyramidal Cells
Tumor Necrosis Factor Receptors
Sciatic Nerve
Dendrites
Synapses
Spine

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Memory deficit
  • Microglia
  • Neuropathic pain
  • SNI
  • Synaptic plasticity
  • TNF-α

Cite this

Liu, Yong ; Zhou, Li Jun ; Wang, Jun ; Li, Dai ; Ren, Wen Jie ; Peng, Jiyun ; Wei, Xiao ; Xu, Ting ; Xin, Wen Jun ; Pang, Rui Ping ; Li, Yong Yong ; Qin, Zhi Hai ; Murugan, Madhuvika ; Mattson, Mark P. ; Wu, Long-Jun ; Liu, Xian Guo. / TNF-α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 4. pp. 871-881.
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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.",
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author = "Yong Liu and Zhou, {Li Jun} and Jun Wang and Dai Li and Ren, {Wen Jie} and Jiyun Peng and Xiao Wei and Ting Xu and Xin, {Wen Jun} and Pang, {Rui Ping} and Li, {Yong Yong} and Qin, {Zhi Hai} and Madhuvika Murugan and Mattson, {Mark P.} and Long-Jun Wu and Liu, {Xian Guo}",
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Liu, Y, Zhou, LJ, Wang, J, Li, D, Ren, WJ, Peng, J, Wei, X, Xu, T, Xin, WJ, Pang, RP, Li, YY, Qin, ZH, Murugan, M, Mattson, MP, Wu, L-J & Liu, XG 2017, 'TNF-α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury', Journal of Neuroscience, vol. 37, no. 4, pp. 871-881. https://doi.org/10.1523/JNEUROSCI.2235-16.2016

TNF-α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. / Liu, Yong; Zhou, Li Jun; Wang, Jun; Li, Dai; Ren, Wen Jie; Peng, Jiyun; Wei, Xiao; Xu, Ting; Xin, Wen Jun; Pang, Rui Ping; Li, Yong Yong; Qin, Zhi Hai; Murugan, Madhuvika; Mattson, Mark P.; Wu, Long-Jun; Liu, Xian Guo.

In: Journal of Neuroscience, Vol. 37, No. 4, 25.01.2017, p. 871-881.

Research output: Contribution to journalArticle

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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

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KW - Microglia

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