Pannexin-1 Deficiency Decreases Epileptic Activity in Mice

Abstract

Objective: 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. Methods 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: 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.

The contribution of astrocyte and neuronal Panx1 to seizures is model and brain region dependent

“…Such interpretation agrees with our previous studies showing that deletion or blockade of Panx1 improves seizure scores (Santiago et al, 2011). Similarly, Panx1 blockade or deletion reduced the duration of afterdischarges and prevented electrical kindling as well as reduced seizure severity and death following systemic PTZ administration (Aquilino et al, 2020).…”

“…showing that Panx1 is upregulated in rodent and human epileptic tissues (Jiang et al, 2013;Li et al, 2017;Mylvaganam et al, 2014;Mylvaganam et al, 2010) and that deletion or blockade of Panx1 attenuates KA-and PTZ-convulsant effects (Aquilino et al, 2020;Dossi et al, 2018;Santiago et al, 2011). In contrast, however, Panx1 activation has been shown to attenuate hyperexcitability under hypoglycemic condition (Kawamura et al, 2010;Kawamura et al, 2014) and to decrease seizure susceptibility in the pilocarpine model (Kim and Kang, 2011).…”

“…Panx1 and acute seizures. The few studies that have addressed the question of whether Panx1 plays a role during the initial phases of acute seizures indicated that, except for the pilocarpine model, deletion or blockade of Panx1 have protective effects (Aquilino et al, 2020;Kim and Kang, 2011;Santiago et al, 2011). Here we show using EEG recordings from Panx1-null mice injected with KA that Panx1 contributed to increase the power spectra, particularly in the beta band, but has no effect on the onsets of the first seizure or status epilepticus.…”

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

“…Recent data suggest that these channels are activated under pathological conditions such as epilepsy and regulate neuronal excitability [ 586 , 592 , 593 , 594 , 595 ]. Pannexin-1 expression seems raised in animal seizure models and in resected human epileptic brain tissue, suggesting relevance to epilepsy [ 586 , 596 , 597 , 598 , 599 ].…”

“…Recently, it was reported that pannexin-1 channel activation promotes seizure generation and maintenance through adenosine triphosphate signaling via purinergic 2 receptors [ 600 ]. Genetic or pharmacological targeting of pannexin-1 channels have anticonvulsant effects in epilepsy models [ 595 , 600 ]. These results suggest that pannexin-1 channel inhibition might represent an alternative therapeutic strategy for treating not only epilepsy but also drug-resistant epilepsy.…”