The role of connexin43 hemichannels in limbic seizures

Nowadays, the contribution of astrocytic connexin43 (Cx43) hemichannels (HCs) to brain functioning and dysfunctioning hasn’t been fully elucidated, mainly because of the paucity of appropriate tools allowing selective targeting of Cx43-HCs. An exception is made for Cx43 mimetic peptides, which inhibit Cx43-HCs but not gap junctions in in vivo settings. In this study, we want to screen Cx43-HCs as novel antiepileptic drug targets through the in vivo screening of a newly developed and selective Cx43-HC-inhibitor (TAT-Gap19 and analogues) in different acute models of seizures. In the acute rat pilocarpine model, we found that an intrahippocampal perfusion of 12.5 µM TAT-Gap19 was able to significantly reduce the seizure-related behavioural movements induced by pilocarpine. Additionally, we still have to determine the concentration of neurotransmitters (e.g. glutamate and D-serine) in the dialysate samples which were collected every 20 min during the previously descbribed experiment. If TAT-Gap19 attenuates the dialysate levels of glutamate and/or D-serine, then most obviously this results from Cx43-HC-blockade and supports the hypothesis that Cx43-HCs release gliotransmitters in vivo. In the six Hertz (6 Hz) mouse model, an electrical model of therapy-resistant seizures, we found that an intracerebroventricular injection of 1 nmol TAT-Gap19 and an intraperitoneal injection of 25 mg/kg TAT-Gap19 leads to a significant decrease in the total mean seizure duration. These results suggest that Cx43-HCs play a role in seizure generation. Additionally, it is of very high importance to screen TAT-Gap19 (and its BBB permeable analogues) in chronic models for epilepsy in order to unravel the role these channels play in epilepsy and epileptogenesis.