Targeting Pannexin1 Improves Seizure Outcome

Abstract

Imbalance of the excitatory neurotransmitter glutamate and of the inhibitory neurotransmitter GABA is one of several causes of seizures. ATP has also been implicated in epilepsy. However, little is known about the mechanisms involved in the release of ATP from cells and the consequences of the altered ATP signaling during seizures. Pannexin1 (Panx1) is found in astrocytes and in neurons at high levels in the embryonic and young postnatal brain, declining in adulthood. Panx1 forms large-conductance voltage sensitive plasma membrane channels permeable to ATP that are also activated by elevated extracellular K+ and following P2 receptor stimulation. Based on these properties, we hypothesized that Panx1 channels may contribute to seizures by increasing the levels of extracellular ATP. Using pharmacological tools and two transgenic mice deficient for Panx1 we show here that interference with Panx1 ameliorates the outcome and shortens the duration of kainic acid-induced status epilepticus. These data thus indicate that the activation of Panx1 in juvenile mouse hippocampi contributes to neuronal hyperactivity in seizures.

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

“…However, a differentiation between the relative contributions of neuronal and glial pannexins on this effect could not be elucidated. The findings by Santiago et al (2011) are in line with an earlier report demonstrating enhanced pannexin mRNA levels in experimental epilepsy (Mylvaganam et al, 2010).…”

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

“…In addition, inflammasome activation has been suggested to have a role in the development of seizures in a pannexin-1-dependent mechanism. 71 Accordingly, kainic acid induces seizures via a mechanism involving opening of pannexin-1 and release of ATP. Moreover, knocking out of pannexin-1 decreases kainic acid-induced seizure duration.…”

Pannexin-1-mediated ATP release from area CA3 drives mGlu5-dependent neuronal oscillations

“…Given the widespread distribution of connexin and pannexin-1 (Panx1) hemichannels on neurones and astrocytes (Cisneros-Mejorado et al, 2014;De Bock et al, 2014) and the strong evidence for a contribution of connexin and pannexin-1 hemichannel-mediated ATP release during neuronal and astrocytic activity (Garre et al, 2010;Santiago et al, 2011;Stout et al, 2002;Suadicani et al, 2012), we decided to test the hypothesis that GI mGluR-evoked ATP release occurs via hemichannels.…”