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Long-Term Potentiation of Glycinergic Synapses Triggered by Interleukin 1Β

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Long-Term Potentiation of Glycinergic Synapses Triggered by Interleukin 1Β Long-term potentiation of glycinergic synapses triggered by interleukin 1β Anda M. Chirila1, Travis E. Brown1,2, Rachel A. Bishop, Nicholas W. Bellono, Francesco G. Pucci, and Julie A. Kauer3 Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912 Edited* by Gina G. Turrigiano, Brandeis University, Waltham, MA, and approved April 18, 2014 (received for review January 17, 2014) Long-term potentiation (LTP) is a persistent increase in synaptic become apparent only when GABAAR and GlyRs are pharma- strength required for many behavioral adaptations, including learn- cologically blocked, indicating that under conditions of disinhibi- ing and memory, visual and somatosensory system functional devel- tion, nonnoxious mechanical stimuli can drive nociceptive-specific opment, and drug addiction. Recent work has suggested a role for projection pathways and elicit allodynia (21). The majority of LTP-like phenomena in the processing of nociceptive information in neurons tested in the dorsal horn receive glycinergic synapses, in- the dorsal horn and in the generation of central sensitization during cluding lamina I projection neurons, both excitatory and inhibitory chronic pain states. Whereas LTP of glutamatergic and GABAergic interneurons of lamina II (22, 23), and inhibitory glycinergic neurons synapses has been characterized throughout the central nervous (24). Given the diversity of afferent targets, it is likely that glycinergic system, to our knowledge there have been no reports of LTP at mam- synapses are differentially modulated in a cell type- and subregion- malian glycinergic synapses. Glycine receptors (GlyRs) are structurally specific manner. For example, during chronic inflammation, pros- related to GABAA receptors and have a similar inhibitory role. Here we taglandin E2 selectively depresses glycinergic synaptic inputs onto report that in the superficial dorsal horn of the spinal cord, glycinergic nonglycinergic neurons (24). Similarly, peripheral nerve injury sup- synapses on inhibitory GABAergic neurons exhibit LTP, occurring rap- presses glycinergic inhibition of a specific excitatory interneuron + idly after exposure to the inflammatory cytokine interleukin-1 beta. class [protein kinase C (PKC)γ neurons receiving Aβ fiber inputs], This form of LTP (GlyR LTP) results from an increase in the number allowing excitatory afferents carrying nonnociceptive tactile infor- and/or change in biophysical properties of postsynaptic glycine recep- mation to activate ascending projections of nociceptive pathways tors. Notably, formalin-induced peripheral inflammation in vivo poten- that are normally under strong inhibitory control (23). tiates glycinergic synapses on dorsal horn neurons, suggesting that Both hyperalgesia and allodynia occur within minutes of pe- GlyR LTP is triggered during inflammatory peripheral injury. Our ripheral inflammation, but the mechanisms underlying these results define a previously unidentified mechanism that could disin- rapid perceptual alterations are poorly understood. The proin- hibit neurons transmitting nociceptive information and may represent flammatory cytokine, IL-1β, is a potent hyperalgesic agent (25– a useful therapeutic target for the treatment of pain. 27), contributing both to peripheral and central sensitization after tissue damage (28–31). Following tissue trauma, nerve in- lycine mediates fast synaptic inhibition throughout the spi- jury, or inflammation, IL-1β levels are up-regulated in the spinal Gnal cord, brainstem, and midbrain, controlling normal mo- cord itself (29, 32, 33), and delivery of IL-1β intrathecally in- tor behavior and rhythm generation, somatosensory processing, creases the activity of superficial dorsal horn neurons that transmit auditory and retinal signaling, and coordination of reflex respon- pain signals to the brain (34, 35). Intrathecal delivery of an IL-1 ses (1). Strychnine-sensitive glycine receptors (GlyRs) are pen- receptor antagonist blocks allodynia in rodent models of inflam- tameric ligand-gated chloride channels of the Cys-loop receptor matory pain (36, 37). A recent study also found that IL-1β ap- family that together with GABAA receptors (GABAARs) dynam- plication rapidly potentiated primary afferent (glutamatergic) ically interact with the synaptic scaffold protein gephyrin to form synapses in dorsal horn slices, through unidentified signaling inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory Significance NEUROSCIENCE processing both during adaptive and pathological pain states (3–7). However, compared with glutamatergic and GABAergic synapses, Whereas glycine is one of the three major neurotransmitters in little is known about the regulation of their synaptic strength. the central nervous system, glycinergic synapses are relatively Several studies have examined glycine receptor trafficking in understudied in intact tissue. Here we provide the first evi- cultured neurons and in heterologous expression systems (8, 9). + dence of long-term potentiation (LTP) at mammalian glycinergic Intracellular Ca2 appears important in the stabilization of GlyRs at 2+ synapses. In the spinal cord dorsal horn, glycinergic synapses on synapses in culture (10), and elevation of intracellular Ca can also inhibitory GABAergic neurons exhibit LTP, occurring rapidly after potently increase glycine receptor single channel openings in cultured exposure to the inflammatory cytokine interleukin-1 beta. This cells and in heterologous systems (11). However, the modulation form of LTP is mediated by postsynaptic alterations in glycine of glycinergic synaptic strength in native tissue remains relatively receptor function. We further show that peripheral inflam- unexplored. mation in vivo triggers glycine receptor LTP. Blocking glycine Following peripheral injury or inflammation, changes in tactile receptor LTP may represent a useful therapeutic strategy in the perception develop, including hyperalgesia (exaggerated pain upon treatment of inflammatory pain. noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the Author contributions: A.M.C., T.E.B., and J.A.K. designed research; A.M.C., T.E.B., R.A.B., confines of the injured region). Inhibitory interneurons of the N.W.B., and F.G.P. performed research; A.M.C., T.E.B., R.A.B., and N.W.B. analyzed data; spinal dorsal horn have been proposed to gate the flow of innoc- and A.M.C., T.E.B., and J.A.K. wrote the paper. uous and nociceptive sensory information from the periphery to The authors declare no conflict of interest. higher brain centers (12), and supportive evidence for this idea is *This Direct Submission article had a prearranged editor. growing (13–17). Loss of GABAergic/glycinergic inhibition con- 1A.M.C. and T.E.B. contributed equally to this work. tributes to enhanced transmission of nociceptive signals through 2Present address: School of Pharmacy, University of Wyoming, Laramie, WY 82071. the dorsal horn circuit during pain states, resulting in hyperalgesia 3To whom correspondence should be addressed. E-mail: [email protected]. – and allodynia (3, 18 20). For example, polysynaptic A-fiber inputs This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. onto neurokinin 1 receptor (NK1R)-expressing projection neurons 1073/pnas.1401013111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1401013111 PNAS | June 3, 2014 | vol. 111 | no. 22 | 8263–8268 Downloaded by guest on April 14, 2020 IL-1β Mediates a Postsynaptic Form of LTP. After brief IL-1β ap- ABplication, IPSC potentiation persisted for the duration of the 500 300 recording, suggesting that it represents a novel form of LTP. To rule out the possibility that residual IL-1β in the slice persistently 400 IL-1β IL-1β activated its receptors even upon wash out, we followed IL-1β 200 300 application with an antagonist of the IL-1 receptor (IL-1RN). Blocking the IL-1 receptor had no effect on established poten- 200 ± – β 100 tiation (IPSC amplitudes: 194.4 24.9% of pre IL-1 values n = P < A B 100 following IL-1RN application; 7; 0.005) (Fig. 2 and ), supporting the idea that IL-1β elicits persistent LTP at glycinergic Normalized GlyR IPSCs Glycinergic IPSCs (pA) 0 0 synapses. The same concentration of IL-1RN entirely prevented 0 10 20 30 40 50 60 70 0 10 20 30 40 50 β Time (min) Time (min) potentiation when applied before IL-1 , as expected if the po- tentiation is mediated through the canonical IL-1 receptor (IPSC amplitudes 14–20 min after IL-1β application in the continued C D GAD65+ cells presence of IL-1RN: 100.3 ± 6.9% of control values; n = 5; not significant, n.s.) (Fig. 2 C and D). * * 500 300 Synaptic potentiation can be maintained by a long-lasting in- crease in neurotransmitter release, or instead by modifications 400 IL-1β IL-1β in postsynaptic receptor number or properties. To test whether 200 300 IL-1β increases postsynaptic glycine receptor sensitivity, we de- livered exogenous glycine in the bathing medium instead of using 200 100 evoked glycine release from nerve terminals. In this experiment, 100 any potentiation must result from enhanced postsynaptic glycine GAD65+ cells receptor function or number. Pulses of exogenous glycine elicited Glycinergic IPSCs (pA) 0 Normalized GlyR IPSCs 0 reproducible inward currents in the recorded neuron. Within 2 min 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 β Time (min)
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