Accumulating evidence shows a key role for astrocytic connexin 43 (Cx43) signaling in epilepsy. However, the lack of experimental distinction between gap junction channels Cx43 (GJC) and hemichannels (HC) has prevented the identification of the exact contribution of either channel configuration to epilepsy. Therefore, we investigated whether TAT-Gap19, a Cx mimetic peptide that inhibits the HCs of Cx43 but not the corresponding GJCs of Cx43, influences experimentally induced seizures in rodents. Dye uptake experiments in acute mouse hippocampal sections 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 concomitant increase in microdialysis levels of D-serine, were suppressed by inhibition of Cx43HC. Furthermore, the anticonvulsant action of TAT-Gap19 was reversed by exogenous administration of D-serine, suggesting that inhibition of Cx43 HC protects against seizures by reducing extracellular levels of D-serine.
The anticonvulsant properties of Cx43 HC inhibition were further confirmed in mouse models with electrical seizures, that is, an acute 6 Hertz (Hz) model of refractory seizures and a 6 Hz chronic corneal activation model. Taken together, these Results indicate that Cx43 HCs play a role in seizures and underscore their potential as a novel drug target in the treatment of epilepsy.