期刊
GLIA
卷 66, 期 8, 页码 1788-1804出版社
WILEY
DOI: 10.1002/glia.23341
关键词
astrocytes; connexin43 hemichannels; pilocarpine; seizures; TAT-Gap19
资金
- Vrije Universiteit Brussel (VUB) [OZR2102]
- European Research Council (ERC) [335476]
- Fund for scientific Research Flanders (FWO Vlaanderen) [G.0298.11, G.0571.12, G.0A54.13, G.0320.15]
- FWO Vlaanderen [G.0A82.13N]
- Interuniversity Attraction Poles Program [P7/10]
- Ghent University (Special Research Fund (BOF)
- Geneeskundige Stichting Koningin Elisabeth [STI.DI2.2017.0004.01]
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.
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