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- Title
TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.
- Authors
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; Murugan, Madhuvika; Mattson, Mark P.; Long-Jun Wu; Xian-Guo Liu
- 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.
- Subjects
NEUROPLASTICITY; HIPPOCAMPUS (Brain); SPINAL cord injuries; PERIPHERAL nerve injuries; MICROGLIA; SCIATIC nerve; DENDRITES
- Publication
Journal of Neuroscience, 2017, Vol 37, Issue 4, p871
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2235-16.2017