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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...

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Autores principales: Spratt, Perry W.E., Alexander, Ryan P.D., Ben-Shalom, Roy, Sahagun, Atehsa, Kyoung, Henry, Keeshen, Caroline M., Sanders, Stephan J., Bender, Kevin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
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.
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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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