Astrocytic connexin 43-hemichannels aggravate seizures by modulating blood-brain barrier permeability in temporal...

The involvement of astrocytic connexin 43 (Cx43) in epileptogenesis has been extensively studied through various approaches, yet the underlying mechanism remains enigmatic. In this study, we explored whether astrocytic Cx43 forms hemichannels (HCs) that contribute to seizure progression in temporal lobe epilepsy (TLE) in mice. We focused on how these HCs influence the permeability of the blood-brain barrier (BBB), a crucial factor in the pathophysiology of epilepsy. Immunofluorescence staining and western blot analysis were employed to assess Cx43 expression in kainic acid-induced TLE mice, while BBB permeability was evaluated in TLE mice and those treated with TAT-Gap19 (an astrocytic Cx43 HC inhibitor) using Evans Blue permeation, serum S100β protein quantification, ZO-1 expression, and albumin extravasation into brain parenchyma via western blotting. Furthermore, seizure burden was monitored continuously using telemetric electroencephalography (EEG) and video monitoring in epileptic and TAT-Gap19-treated mice. Results demonstrated a significant increase in Cx43 content in hippocampal tissue in the TLE group, with a pronounced expression around blood vessels. TAT-GAP19 treatment alleviated EEG seizures and BBB permeability in TLE mice. These findings suggest that astrocytic Cx43 HCs in the hippocampus play a crucial role in epileptogenesis and seizure progression by regulating BBB permeability. Targeting Cx43-formed HCs distributed around the neurovascular unit may offer a novel therapeutic approach for epilepsy.