Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing
Abstract Mutations of the Na+-activated K+ channel Slack (KCNT1) are associated with terrible epilepsy syndromes that already begin in infancy. Here we report increased severity of acute kainic acid-induced seizures in adult and juvenile Slack knockout mice (Slack−/−) in vivo. Fittingly, we find exa...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05387-9 |
| _version_ | 1827708975482667008 |
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| author | David Skrabak Helmut Bischof Thomas Pham Peter Ruth Rebekka Ehinger Lucas Matt Robert Lukowski |
| author_facet | David Skrabak Helmut Bischof Thomas Pham Peter Ruth Rebekka Ehinger Lucas Matt Robert Lukowski |
| author_sort | David Skrabak |
| collection | DOAJ |
| description | Abstract Mutations of the Na+-activated K+ channel Slack (KCNT1) are associated with terrible epilepsy syndromes that already begin in infancy. Here we report increased severity of acute kainic acid-induced seizures in adult and juvenile Slack knockout mice (Slack−/−) in vivo. Fittingly, we find exacerbation of cell death following kainic acid exposure in organotypic hippocampal slices as well as dissociated hippocampal cultures from Slack−/− in vitro. Furthermore, in cultured Slack−/− neurons, kainic acid-triggered Ca2+ influx and K+ efflux as well as depolarization-induced tetrodotoxin-sensitive inward currents are higher compared to the respective controls. This apparent changes in ion homeostasis could possibly explain altered action potential kinetics of Slack−/− neurons: steeper rise slope, decreased threshold, and duration of afterhyperpolarization, which ultimately lead to higher action potential frequencies during kainic acid application or injection of depolarizing currents. Based on our data, we propose Slack as crucial gatekeeper of neuronal excitability to acutely limit seizure severity. |
| first_indexed | 2024-03-10T17:14:23Z |
| format | Article |
| id | doaj.art-a6c08612daa049a9a70afd552cb8e96a |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:23Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-a6c08612daa049a9a70afd552cb8e96a2023-11-20T10:34:25ZengNature PortfolioCommunications Biology2399-36422023-10-016111210.1038/s42003-023-05387-9Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firingDavid Skrabak0Helmut Bischof1Thomas Pham2Peter Ruth3Rebekka Ehinger4Lucas Matt5Robert Lukowski6Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of TübingenAbstract Mutations of the Na+-activated K+ channel Slack (KCNT1) are associated with terrible epilepsy syndromes that already begin in infancy. Here we report increased severity of acute kainic acid-induced seizures in adult and juvenile Slack knockout mice (Slack−/−) in vivo. Fittingly, we find exacerbation of cell death following kainic acid exposure in organotypic hippocampal slices as well as dissociated hippocampal cultures from Slack−/− in vitro. Furthermore, in cultured Slack−/− neurons, kainic acid-triggered Ca2+ influx and K+ efflux as well as depolarization-induced tetrodotoxin-sensitive inward currents are higher compared to the respective controls. This apparent changes in ion homeostasis could possibly explain altered action potential kinetics of Slack−/− neurons: steeper rise slope, decreased threshold, and duration of afterhyperpolarization, which ultimately lead to higher action potential frequencies during kainic acid application or injection of depolarizing currents. Based on our data, we propose Slack as crucial gatekeeper of neuronal excitability to acutely limit seizure severity.https://doi.org/10.1038/s42003-023-05387-9 |
| spellingShingle | David Skrabak Helmut Bischof Thomas Pham Peter Ruth Rebekka Ehinger Lucas Matt Robert Lukowski Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing Communications Biology |
| title | Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing |
| title_full | Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing |
| title_fullStr | Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing |
| title_full_unstemmed | Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing |
| title_short | Slack K+ channels limit kainic acid-induced seizure severity in mice by modulating neuronal excitability and firing |
| title_sort | slack k channels limit kainic acid induced seizure severity in mice by modulating neuronal excitability and firing |
| url | https://doi.org/10.1038/s42003-023-05387-9 |
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