Pannexin-1 Deficiency Decreases Epileptic Activity in Mice

• Main Authors: Mark S. Aquilino, Paige Whyte-Fagundes, Mark K. Lukewich, Liang Zhang, Berj L. Bardakjian, Georg R. Zoidl, Peter L. Carlen
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: International Journal of Molecular Sciences
• Subjects: panx1; seizure; epilepsy; PTZ; 4-AP; kindling
• Online Access: https://www.mdpi.com/1422-0067/21/20/7510
• ISSN: 1661-6596; 1422-0067

Objective<i>: </i>Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. <i>Methods </i>Control and Panx1 knockout C57Bl/6 mice of both sexes were monitored for their behavioral and electrographic responses to seizure-generating stimuli in three epilepsy models—(1) systemic injection of pentylenetetrazol, (2) acute electrical kindling of the hippocampus and (3) neocortical slice exposure to 4-aminopyridine. Phase-amplitude cross-frequency coupling was used to assess changes in an epileptogenic state resulting from Panx1 deletion. Results<i>: </i>Seizure activity was suppressed in Panx1 knockouts and by application of Panx1 channel blockers, Brilliant Blue-FCF and probenecid, across all epilepsy models. In response to pentylenetetrazol, WT mice spent a greater proportion of time experiencing severe (stage 6) seizures as compared to Panx1-deficient mice. Following electrical stimulation of the hippocampal CA3 region, Panx1 knockouts had significantly shorter evoked afterdischarges and were resistant to kindling. In response to 4-aminopyridine, neocortical field recordings in slices of Panx1 knockout mice showed reduced instances of electrographic seizure-like events. Cross-frequency coupling analysis of these field potentials highlighted a reduced coupling of excitatory delta–gamma and delta-HF rhythms in the Panx1 knockout. Significance: These results suggest that Panx1 plays a pivotal role in maintaining neuronal hyperexcitability in epilepsy models and that genetic or pharmacological targeting of Panx1 has anti-convulsant effects.