Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy

Abstract

Epilepsies are characterized by recurrent seizures, which disrupt normal brain function. Alterations in neuronal excitability and excitation-inhibition balance have been shown to promote seizure generation, yet molecular determinants of such alterations remain to be identified. Pannexin channels are nonselective, large-pore channels mediating extracellular exchange of neuroactive molecules. Recent data suggest that these channels are activated under pathological conditions and regulate neuronal excitability. However, whether pannexin channels sustain or counteract chronic epilepsy in human patients remains unknown. We studied the impact of pannexin-1 channel activation in postoperative human tissue samples from patients with epilepsy displaying epileptic activity ex vivo. These samples were obtained from surgical resection of epileptogenic zones in patients suffering from lesional or drug-resistant epilepsy. We found that pannexin-1 channel activation promoted seizure generation and maintenance through adenosine triphosphate signaling via purinergic 2 receptors. Pharmacological inhibition of pannexin-1 channels with probenecid or mefloquine-two medications currently used for treating gout and malaria, respectively-blocked ictal discharges in human cortical brain tissue slices. Genetic deletion of pannexin-1 channels in mice had anticonvulsant effects when the mice were exposed to kainic acid, a model of temporal lobe epilepsy. Our data suggest a proepileptic role of pannexin-1 channels in chronic epilepsy in human patients and that pannexin-1 channel inhibition might represent an alternative therapeutic strategy for treating lesional and drug-resistant epilepsies.

Gamma‐aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia

“…16,25,29 Furthermore, IIDs were found to be focal and generated at a similar site in consecutive slices from the same tissue, indicating that local preexisting modifications are involved in the response rather than direct traumatism related to the slicing procedure. The size of our cohort is small and based on variable FCD subtypes.…”

“…However, in our past studies, spontaneous epileptic activities have never been recorded in vitro from control human tissue. 16,25,29 Furthermore, IIDs were found to be focal and generated at a similar site in consecutive slices from the same tissue, indicating that local preexisting modifications are involved in the response rather than direct traumatism related to the slicing procedure. The morphological histological analysis was performed on 8% of the samples, and therefore these results need to be carefully interpreted.…”

“…Previous studies reported several possible mechanisms underlying the epileptogenicity in FCD. 25 Here, we focused specifically on GABAergic mechanisms. 7,[33][34][35] Alteration of the extracellular matrix through increased expression of metalloproteinase 9 leading to putative modified intra-and extracellular chloride levels has been reported.…”

“…25 We included in this study only the slices generating spontaneous IIDs. Twenty-nine cortical slices were placed on planar microelectrode array (MEA) petri Pharmacological studies for IIDs were performed in modified physiological ACSF containing bumetanide (8 μM) or picrotoxin (100 μM).…”

“…In humans, such low Mg 2+ /high K + proconvulsant solution triggers seizurelike events in vitro only in cortex from epileptic patients in which spontaneous IIDs are recorded. 25 We included in this study only the slices generating spontaneous IIDs.…”