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-␣) 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.Key words: memory deficit; microglia; neuropathic pain; SNI; synaptic plasticity; TNF-␣ Significance StatementChronic 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 regiondependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury.

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

“…A mouse model of chronic constriction injury of the sciatic nerve reduced neurite length in GABA neurons within lamina II of the spinal cord [50]. Another group observed that following spared nerve injury, there were decreases in the number of branches and neurite length of hippocampal neurons but increases in spinal dorsal horn neurons [51]. Together these studies, along with those reported here, suggest adaptations of the central nervous system to chronic pain culminate in alteration of the neuronal cytoarchitecture.…”

Optogenetic activation of spinal microglia triggers chronic pain in mice

“…We also found that ReaChR is widely expressed in different brain regions such as the hippocampus and cortex. Therefore, CX3CR1 creER/+ : R26 LSL-ReaChR/+ transgenic mice will be a useful tool to study supraspinal microglia in brain function, such as pain-related comorbidity 53 , memory 54 , and epilepsy 55 There are two potential consequences after ReaChR activation, including membrane depolarization and Ca 2+ elevation. Currently, we know little about the function of membrane potential alterations in microglia function.…”

Distinct roles of srGAP3‐Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel

“…For the requirements of the tested segments, protrusions on successive dendritic segments within 50–130 µm away from the centre of the soma were examined regardless of whether they were from primary, secondary or tertiary dendritic branches (Liu et al . 2017; Pyronneau et al . 2017).…”