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.

Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain

“…However, this notion is based on in vitro analysis of cellular responses to LPS or cytokine administration (Corona, et al 2010; Guillemin, et al 2003) (Chiarugi, et al 2001; Schwarcz and Stone 2017). Consistent with a recent report (Liu, et al 2017), we also observed activation of microglia in the hippocampus in response to SNI. However, we observed that in response to SNI, KMO protein was mainly increased in NeuN-positive neuronal cells in the hippocampal dentate gyrus and not in the microglia.…”

LRP1 deficiency in microglia blocks neuro‐inflammation in the spinal dorsal horn and neuropathic pain processing

“…We now show that expression of the equivalent cytokines is decreased in the SDH following PNL in mice with LRP1-deficient microglia. TNFα, IL-6, and IL-1β are known to modulate spinal cord synaptic transmission and play an important role in central sensitization (Kawasaki, Zhang, Cheng, & Ji, 2008;Liu et al, 2017;Obreja, Rathee, Lips, Distler, & Kress, 2002). Thus, the absence of demonstrable tactile allodynia in TAM-treated Cx3cr1-CreER T -LRP1 fl/fl mice may reflect either direct interaction of sLRP1 with SDH neurons or changes in the local concentration of other factors, such as TNFα, IL-6, and IL-1β, secondary to sLRP1-induced gene regulatory events.…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…Descending facilitation of neuropathic pain from the PAG is promoted by such glial cell activation in a CCI model [103]. The hippocampus has been reported to exhibit impaired longterm potentiation in SNI mice, an effect that was recently suggested to originate from the effects of tumor necrosis factor-alpha and microglial activation in this brain region [104]. This glia-driven change in synaptic plasticity and resultant mechanical hypersensitivity has also been reported in the primary somatosensory cortex in a mouse SNL model [105•].…”