Cargando…

Pannexin-1 Deficiency Decreases Epileptic Activity in Mice

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 C...

Descripción completa

Detalles Bibliográficos
Autores principales: Aquilino, Mark S., Whyte-Fagundes, Paige, Lukewich, Mark K., Zhang, Liang, Bardakjian, Berj L., Zoidl, Georg R., Carlen, Peter L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589538/
https://www.ncbi.nlm.nih.gov/pubmed/33053775
http://dx.doi.org/10.3390/ijms21207510
_version_ 1783600601412665344
author Aquilino, Mark S.
Whyte-Fagundes, Paige
Lukewich, Mark K.
Zhang, Liang
Bardakjian, Berj L.
Zoidl, Georg R.
Carlen, Peter L.
author_facet Aquilino, Mark S.
Whyte-Fagundes, Paige
Lukewich, Mark K.
Zhang, Liang
Bardakjian, Berj L.
Zoidl, Georg R.
Carlen, Peter L.
author_sort Aquilino, Mark S.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7589538
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-75895382020-10-29 Pannexin-1 Deficiency Decreases Epileptic Activity in Mice Aquilino, Mark S. Whyte-Fagundes, Paige Lukewich, Mark K. Zhang, Liang Bardakjian, Berj L. Zoidl, Georg R. Carlen, Peter L. Int J Mol Sci Article 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. MDPI 2020-10-12 /pmc/articles/PMC7589538/ /pubmed/33053775 http://dx.doi.org/10.3390/ijms21207510 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Aquilino, Mark S.
Whyte-Fagundes, Paige
Lukewich, Mark K.
Zhang, Liang
Bardakjian, Berj L.
Zoidl, Georg R.
Carlen, Peter L.
Pannexin-1 Deficiency Decreases Epileptic Activity in Mice
title Pannexin-1 Deficiency Decreases Epileptic Activity in Mice
title_full Pannexin-1 Deficiency Decreases Epileptic Activity in Mice
title_fullStr Pannexin-1 Deficiency Decreases Epileptic Activity in Mice
title_full_unstemmed Pannexin-1 Deficiency Decreases Epileptic Activity in Mice
title_short Pannexin-1 Deficiency Decreases Epileptic Activity in Mice
title_sort pannexin-1 deficiency decreases epileptic activity in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589538/
https://www.ncbi.nlm.nih.gov/pubmed/33053775
http://dx.doi.org/10.3390/ijms21207510
work_keys_str_mv AT aquilinomarks pannexin1deficiencydecreasesepilepticactivityinmice
AT whytefagundespaige pannexin1deficiencydecreasesepilepticactivityinmice
AT lukewichmarkk pannexin1deficiencydecreasesepilepticactivityinmice
AT zhangliang pannexin1deficiencydecreasesepilepticactivityinmice
AT bardakjianberjl pannexin1deficiencydecreasesepilepticactivityinmice
AT zoidlgeorgr pannexin1deficiencydecreasesepilepticactivityinmice
AT carlenpeterl pannexin1deficiencydecreasesepilepticactivityinmice