Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Abstract

Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

Interleukin-1 receptor type 1 is overexpressed in neurons but not in glial cells within the rat superficial spinal dorsal horn in complete Freund adjuvant-induced inflammatory pain

“…We found that approximately 10% of IL-1R1 immunostaining on the somatodendritic membrane of neurons was co-localized with gephyrin, a scaffolding protein within the postsynaptic membrane of inhibitory synapses [86–88]. In the light of the report of Chirila et al [99], showing that in the superficial spinal dorsal horn glycinergic synapses on inhibitory GABAergic, neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine IL-1β, it is likely that the gephyrin-immunostained spots found to be positive also for IL-1R1 in the present study represent glycinergic synapses. Although we observed IL-1R1 immunostaining only in approximately 1% of gephyrin-immunostained spots, one can regard this finding functionally significant, since the potentiation of glycinergic synapses on GABAergic neurons evoked by in vitro bath application of IL-1β [21, 100] or peripheral inflammation in vivo [99] could evoke considerable disinhibition in pain processing spinal neural networks [21, 101], an important mechanism that is increasingly appreciated for the generation of chronic pain [102, 103].…”

Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway

“…The impaired morphology, function even death of neurons might be consequences of excessive IL-1b release (Kuhn, 2014). Meanwhile, IL-1b exposure induced LTP in inhibitory GABAergic neurons contributed to somatosensory changes which is another mechanism underlying the development of morphine tolerance (Chirila et al, 2014).…”

Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord

“…Mechanistically, activation of p38 in microglia results in increased synthesis of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Xu et al, 2013a; Ji and Suter, 2007; Clark et al, 2006; Berta et al, 2014). These cytokines play a critical role in inducing hyperactivity of dorsal horn neurons resulting in pain hypersensitivity (Kawasaki et al, 2008; Ren and Torres, 2009; Zhang et al, 2010; Park et al, 2011; Yan and Weng, 2013; Chirila et al, 2014). Microglial activation was thought to play a role in both sexes (Chen et al, 2012; Cho et al, 2006; Ledeboer et al, 2005), however, it is incompletely known whether p38 signaling in microglia is sex-dependent.…”