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Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells
Loss-of-function variants in the gene SCN2A, which encodes the sodium channel Na(V)1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20%–30% of children with these variants also suffer from epilepsy, with altered neuronal activity originating in neo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719649/ https://www.ncbi.nlm.nih.gov/pubmed/34348157 http://dx.doi.org/10.1016/j.celrep.2021.109483 |
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author | Spratt, Perry W.E. Alexander, Ryan P.D. Ben-Shalom, Roy Sahagun, Atehsa Kyoung, Henry Keeshen, Caroline M. Sanders, Stephan J. Bender, Kevin J. |
author_facet | Spratt, Perry W.E. Alexander, Ryan P.D. Ben-Shalom, Roy Sahagun, Atehsa Kyoung, Henry Keeshen, Caroline M. Sanders, Stephan J. Bender, Kevin J. |
author_sort | Spratt, Perry W.E. |
collection | PubMed |
description | Loss-of-function variants in the gene SCN2A, which encodes the sodium channel Na(V)1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20%–30% of children with these variants also suffer from epilepsy, with altered neuronal activity originating in neocortex, a region where Na(V)1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking Na(V)1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic-clamp recordings revealed that Na(V)1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may, therefore, account for why SCN2A loss-of-function can paradoxically promote seizure. |
format | Online Article Text |
id | pubmed-8719649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-87196492021-12-31 Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells Spratt, Perry W.E. Alexander, Ryan P.D. Ben-Shalom, Roy Sahagun, Atehsa Kyoung, Henry Keeshen, Caroline M. Sanders, Stephan J. Bender, Kevin J. Cell Rep Article Loss-of-function variants in the gene SCN2A, which encodes the sodium channel Na(V)1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20%–30% of children with these variants also suffer from epilepsy, with altered neuronal activity originating in neocortex, a region where Na(V)1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking Na(V)1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic-clamp recordings revealed that Na(V)1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may, therefore, account for why SCN2A loss-of-function can paradoxically promote seizure. 2021-08-03 /pmc/articles/PMC8719649/ /pubmed/34348157 http://dx.doi.org/10.1016/j.celrep.2021.109483 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Spratt, Perry W.E. Alexander, Ryan P.D. Ben-Shalom, Roy Sahagun, Atehsa Kyoung, Henry Keeshen, Caroline M. Sanders, Stephan J. Bender, Kevin J. Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells |
title | Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells |
title_full | Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells |
title_fullStr | Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells |
title_full_unstemmed | Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells |
title_short | Paradoxical hyperexcitability from Na(V)1.2 sodium channel loss in neocortical pyramidal cells |
title_sort | paradoxical hyperexcitability from na(v)1.2 sodium channel loss in neocortical pyramidal cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719649/ https://www.ncbi.nlm.nih.gov/pubmed/34348157 http://dx.doi.org/10.1016/j.celrep.2021.109483 |
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