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Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels

Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range...

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Autores principales: Alexander, Ryan P.D., Mitry, John, Sareen, Vasu, Khadra, Anmar, Bowie, Derek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553571/
https://www.ncbi.nlm.nih.gov/pubmed/31110133
http://dx.doi.org/10.1523/ENEURO.0126-19.2019
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author Alexander, Ryan P.D.
Mitry, John
Sareen, Vasu
Khadra, Anmar
Bowie, Derek
author_facet Alexander, Ryan P.D.
Mitry, John
Sareen, Vasu
Khadra, Anmar
Bowie, Derek
author_sort Alexander, Ryan P.D.
collection PubMed
description Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range. AP frequency is shaped by the activity of somatodendritic A-type K(+) channels and the inhibitory effect of GABAergic transmission. An added complication, however, is that whole-cell recording from SCs induces a time-dependent and sustained increase in membrane excitability making it difficult to define the full range of firing rates. Here, we show that whole-cell recording in cerebellar SCs of both male and female mice augments firing rates by reducing the membrane potential at which APs are initiated. AP threshold is lowered due to a hyperpolarizing shift in the gating behavior of voltage-gated Na(+) channels. Whole-cell recording also elicits a hyperpolarizing shift in the gating behavior of A-type K(+) channels which contributes to increased firing rates. Hodgkin–Huxley modeling and pharmacological experiments reveal that gating shifts in A-type K(+) channel activity do not impact AP threshold, but rather promote channel inactivation which removes restraint on the upper limit of firing rates. Taken together, our work reveals an unappreciated impact of voltage-gated Na(+) channels that work in coordination with A-type K(+) channels to regulate the firing frequency of cerebellar SCs.
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spelling pubmed-65535712019-06-07 Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels Alexander, Ryan P.D. Mitry, John Sareen, Vasu Khadra, Anmar Bowie, Derek eNeuro New Research Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range. AP frequency is shaped by the activity of somatodendritic A-type K(+) channels and the inhibitory effect of GABAergic transmission. An added complication, however, is that whole-cell recording from SCs induces a time-dependent and sustained increase in membrane excitability making it difficult to define the full range of firing rates. Here, we show that whole-cell recording in cerebellar SCs of both male and female mice augments firing rates by reducing the membrane potential at which APs are initiated. AP threshold is lowered due to a hyperpolarizing shift in the gating behavior of voltage-gated Na(+) channels. Whole-cell recording also elicits a hyperpolarizing shift in the gating behavior of A-type K(+) channels which contributes to increased firing rates. Hodgkin–Huxley modeling and pharmacological experiments reveal that gating shifts in A-type K(+) channel activity do not impact AP threshold, but rather promote channel inactivation which removes restraint on the upper limit of firing rates. Taken together, our work reveals an unappreciated impact of voltage-gated Na(+) channels that work in coordination with A-type K(+) channels to regulate the firing frequency of cerebellar SCs. Society for Neuroscience 2019-06-04 /pmc/articles/PMC6553571/ /pubmed/31110133 http://dx.doi.org/10.1523/ENEURO.0126-19.2019 Text en Copyright © 2019 Alexander et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Alexander, Ryan P.D.
Mitry, John
Sareen, Vasu
Khadra, Anmar
Bowie, Derek
Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels
title Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels
title_full Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels
title_fullStr Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels
title_full_unstemmed Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels
title_short Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na(+) and A-Type K(+) Channels
title_sort cerebellar stellate cell excitability is coordinated by shifts in the gating behavior of voltage-gated na(+) and a-type k(+) channels
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553571/
https://www.ncbi.nlm.nih.gov/pubmed/31110133
http://dx.doi.org/10.1523/ENEURO.0126-19.2019
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