Targeting Pannexin1 Improves Seizure Outcome

Marcelo F Santiago,Anne Charollais,Dorothee Caille,Sarah E Lutz,Eliana Scemes,Jana Veliskova,Naman K Patel,Paolo Meda,Steven Barnes

doi:10.1371/journal.pone.0025178

Marcelo F Santiago, Anne Charollais + Show 7 more

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https://doi.org/10.1371/journal.pone.0025178

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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.

Highlights

Among the various types of paracrine signals, purinergic ATPmediated signaling is emerging as one of the most prominent form involved in neural cell interactions
High extracellular potassium opens Panx1 channels in hippocampal slices We evaluated whether Panx1 channels were activated under conditions of neuronal hyperactivity by measuring the cellular influx of YoPro1 in hippocampal slices exposed for 1 hr to artificial cerebrospinal fluid (ACSF) containing 10 mM K+
The data are consistent with a model in which the intense neuronal activity that occurs during epileptiform activity elevates extracellular K+

Summary

Introduction

Among the various types of paracrine signals, purinergic ATPmediated signaling is emerging as one of the most prominent form involved in neural cell interactions (reviewed in [1]). This is because all neural cell types are able to release and respond to ATP and/or its metabolites. Pannexins (Panx 1, 2, and 3) are a group of proteins that share sequence homologies with the invertebrate gap junction proteins, the innexins. From their homologues, pannexins do not form gap junction intercellular channels, but do form plasma membrane channels, at least in the case of Panx. Panx transcripts have been shown to be expressed in the CNS, at high levels in early stages of murine brain development, decreasing in adulthood [6]

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