Dataset Information

TNF-? 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-?) 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-? 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-? 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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5296781 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

Liu Yong Y Zhou Li-Jun LJ Wang Jun J Li Dai D Ren Wen-Jie WJ Peng Jiyun J Peng Jiyun J Wei Xiao X Xu Ting T Xin Wen-Jun WJ Pang Rui-Ping RP Li Yong-Yong YY Qin Zhi-Hai ZH Murugan Madhuvika M Mattson Mark P MP Wu Long-Jun LJ Liu Xian-Guo XG

The Journal of neuroscience : the official journal of the Society for Neuroscience 20170101 4

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. H ...[more]

PMID: 28123022

Similar Datasets

Project description:Sigma-1 Receptor has been shown to localize to sites of peripheral nerve injury and back pain. Radioligand probes have been developed to localize Sigma-1 Receptor and thus image pain source. However, in non-pain conditions, Sigma-1 Receptor expression has also been demonstrated in the central nervous system and dorsal root ganglion. This work aimed to study Sigma-1 Receptor expression in a microglial cell population in the lumbar spine following peripheral nerve injury. A publicly available transcriptomic dataset of 102,691 L4/5 mouse microglial cells from a sciatic-sural nerve spared nerve injury model and 93,027 age and sex matched cells from a sham model was used. At each of three time points-postoperative day 3, postoperative day 14, and postoperative month 5-gene expression data was recorded for both spared nerve injury and Sham cell groups. For all cells, 27,998 genes were sequenced. All cells were clustered into 12 distinct subclusters and gene set enrichment pathway analysis was performed. For both the spared nerve injury and Sham groups, Sigma-1 Receptor expression significantly decreased at each time point following surgery. At the 5-month postoperative time point, only one of twelve subclusters showed significantly increased Sigma-1 Receptor expression in spared nerve injury cells as compared to Sham cells (p = 0.0064). Pathway analysis of this cluster showed a significantly increased expression of the inflammatory response pathway in the spared nerve injury cells relative to Sham cells at the 5-month time point (p = 6.74e-05). A distinct subcluster of L4/5 microglia was identified which overexpress Sigma-1 Receptor following peripheral nerve injury consistent with neuropathic pain inflammatory response functioning. This indicates that upregulated Sigma-1 Receptor in the central nervous system characterizes post-acute peripheral nerve injury and may be further developed for clinical use in the differentiation between low back pain secondary to peripheral nerve injury and low back pain not associated with peripheral nerve injury in cases where the pain cannot be localized.

Project description:BackgroundGlial cells are involved in the synaptic elimination process that follows neuronal lesions, and are also responsible for mediating the interaction between the nervous and immune systems. Neurons and glial cells express Toll-like receptors (TLRs), which may affect the plasticity of the central nervous system (CNS). Because TLRs might also have non-immune functions in spinal-cord injury (SCI), we aimed to investigate the influence of TLR2 and TLR4 on synaptic plasticity and glial reactivity after peripheral nerve axotomy.MethodsThe lumbar spinal cords of C3H/HePas wild-type (WT) mice, C3H/HeJ TLR4-mutant mice, C57BL/6J WT mice, and C57BL/6J TLR2 knockout (KO) mice were studied after unilateral sciatic nerve transection. The mice were killed via intracardiac perfusion, and the spinal cord was processed for immunohistochemistry, transmission electron microscopy (TEM), western blotting, cell culture, and reverse transcriptase PCR. Primary cultures of astrocytes from newborn mice were established to study the astrocyte response in the absence of TLR2 and the deficiency of TLR4 expression.ResultsThe results showed that TLR4 and TLR2 expression in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord. First, TLR4 contributed to synaptic preservation of terminals in apposition to lesioned motor neurons after peripheral injury, regardless of major histocompatibility complex class I (MHC I) expression. In addition, in the presence of TLR4, there was upregulation of glial cell-derived neurotrophic factor and downregulation of interleukin-6, but no morphological differences in glial reactivity were seen. By contrast, TLR2 expression led to greater synaptic loss, correlating with increased astrogliosis and upregulation of pro-inflammatory interleukins. Moreover, the absence of TLR2 resulted in the upregulation of neurotrophic factors and MHC I expression.ConclusionTLR4 and TLR2 in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord and in astroglial reactions, indicating possible roles for these proteins in neuronal and glial responses to injury.

Dataset Information

TNF-? Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

Publications

TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets