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TARP γ-2 is required for inflammation-associated AMPA receptor plasticity within lamina II of the spinal cord dorsal horn

Sullivan, SJ; Farrant, M; Cull-Candy, SG; (2017) TARP γ-2 is required for inflammation-associated AMPA receptor plasticity within lamina II of the spinal cord dorsal horn. Journal of Neuroscience , 37 (25) pp. 6007-6020. 10.1523/JNEUROSCI.0772-16.2017. Green open access

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Abstract

In the brain, transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn (SDH), an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking stargazer (stg/stg) mice. Examination of EPSCs revealed the targeting of γ-2 to be synapse specific; the amplitude of spontaneously occurring mEPSCs was reduced in neurons from stg/stg mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that γ-2 is associated with AMPARs at synapses in lamina ll but excluded from those at C-fiber inputs, a view supported by our immunohistochemical co-labeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium permeable (CP-) AMPARs. This effect was abolished in stg/stg mice. Our results establish that while γ-2 is not typically associated with calcium-impermeable (CI-) AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation.SIGNIFICANCE STATEMENTIn the brain, transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) critically determine the functional properties of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. An increase in the excitability of neurons within the superficial dorsal horn (SDH) of the spinal cord is thought to underlie heighted pain sensitivity. One mechanism considered to contribute to such long-lived changes is the remodeling of the ionotropic AMPA-type glutamate receptors that underlie fast excitatory synaptic transmission in the SDH. Here we show that the TARP γ-2 (stargazin) is present in SDH neurons and is necessary in a form of inflammatory pain-induced plasticity, which involves an increase in the prevalence of synaptic calcium-permeable AMPARs.

Type: Article
Title: TARP γ-2 is required for inflammation-associated AMPA receptor plasticity within lamina II of the spinal cord dorsal horn
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.0772-16.2017
Publisher version: http://dx.doi.org/10.1523/JNEUROSCI.0772-16.2017
Language: English
Additional information: Copyright © 2017 Sullivan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: AMPARs, dorsal horn, inflammation, spinal cord, stargazin, TARPs
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1558556
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