Inhibition of astroglial connexin43 hemichannels with TAT‐Gap19 exerts anticonvulsant effects in rodents. Issue 8 (23rd April 2018)

• Record Type: Journal Article
• Authors: Walrave, Laura; Pierre, Anouk; Albertini, Giulia; Aourz, Najat; De Bundel, Dimitri; Van Eeckhaut, Ann; Vinken, Mathieu; Giaume, Christian; Leybaert, Luc; Smolders, Ilse
• Is Part Of: Glia. Volume 66:Issue 8(2018)
• Page Start: 1788
• Page End: 1804
• Publication Date: 2018-04-23
• Subjects: astrocytes -- connexin43 hemichannels -- pilocarpine -- seizures -- TAT‐Gap19; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23341
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: Accumulating evidence shows a key function for astrocytic connexin43 (Cx43) signaling in epilepsy. However, the lack of experimental distinction between Cx43 gap junction channels (GJCs) and hemichannels (HCs) has impeded the identification of the exact contribution of either channel configurations to epilepsy. We therefore investigated whether TAT‐Gap19, a Cx mimetic peptide that inhibits Cx43 HCs but not the corresponding Cx43 GJCs, influences experimentally induced seizures in rodents. Dye uptake experiments in acute hippocampal slices of mice demonstrated that astroglial Cx43 HCs open in response to the chemoconvulsant pilocarpine and this was inhibited by TAT‐Gap19. In vivo, pilocarpine‐induced seizures as well as the accompanying increase in D‐serine microdialysate levels were suppressed by Cx43 HC inhibition. Moreover, the anticonvulsant action of TAT‐Gap19 was reversed by exogenous D‐serine administration, suggesting that Cx43 HC inhibition protects against seizures by lowering extracellular D‐serine levels. The anticonvulsive properties of Cx43 HC inhibition were further confirmed in electrical seizure mouse models, i.e . an acute 6 Hertz (Hz) model of refractory seizures and a chronic 6 Hz corneal kindling model. Collectively, these results indicate that Cx43 HCs play a role in seizures and underscore their potential as a novel and druggable target in epilepsy treatment. Main Points: Astrocytic Cx43 HCs open in response to pilocarpine. Cx43 HC inhibition diminishes pilocarpine‐induced seizures and extracellular D‐serine levels in vivo . Cx43 HC inhibition suppresses electrically‐induced refractory seizures.