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Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis
Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABA(A) receptors (GABA(A)Rs). The impact of changes in steady state Cl(−) gradient is relatively straightforward to understand, but how dynamic interplay between Cl(−) influx, diffusion, extrusio...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169517/ https://www.ncbi.nlm.nih.gov/pubmed/21931544 http://dx.doi.org/10.1371/journal.pcbi.1002149 |
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author | Doyon, Nicolas Prescott, Steven A. Castonguay, Annie Godin, Antoine G. Kröger, Helmut De Koninck, Yves |
author_facet | Doyon, Nicolas Prescott, Steven A. Castonguay, Annie Godin, Antoine G. Kröger, Helmut De Koninck, Yves |
author_sort | Doyon, Nicolas |
collection | PubMed |
description | Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABA(A) receptors (GABA(A)Rs). The impact of changes in steady state Cl(−) gradient is relatively straightforward to understand, but how dynamic interplay between Cl(−) influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl(−) load on a fast time scale, whereas Cl(−)extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl(−) gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABA(A)R-mediated inhibition, but increasing GABA(A)R input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl(−). Furthermore, if spiking persisted despite the presence of GABA(A)R input, Cl(−) accumulation became accelerated because of the large Cl(−) driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl(−) and pH regulation. Several model predictions were tested and confirmed by [Cl(−)](i) imaging experiments. Our study has thus uncovered how Cl(−) regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K(−) accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention. |
format | Online Article Text |
id | pubmed-3169517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31695172011-09-19 Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis Doyon, Nicolas Prescott, Steven A. Castonguay, Annie Godin, Antoine G. Kröger, Helmut De Koninck, Yves PLoS Comput Biol Research Article Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABA(A) receptors (GABA(A)Rs). The impact of changes in steady state Cl(−) gradient is relatively straightforward to understand, but how dynamic interplay between Cl(−) influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl(−) load on a fast time scale, whereas Cl(−)extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl(−) gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABA(A)R-mediated inhibition, but increasing GABA(A)R input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl(−). Furthermore, if spiking persisted despite the presence of GABA(A)R input, Cl(−) accumulation became accelerated because of the large Cl(−) driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl(−) and pH regulation. Several model predictions were tested and confirmed by [Cl(−)](i) imaging experiments. Our study has thus uncovered how Cl(−) regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K(−) accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention. Public Library of Science 2011-09-08 /pmc/articles/PMC3169517/ /pubmed/21931544 http://dx.doi.org/10.1371/journal.pcbi.1002149 Text en Doyon et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Doyon, Nicolas Prescott, Steven A. Castonguay, Annie Godin, Antoine G. Kröger, Helmut De Koninck, Yves Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis |
title | Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis |
title_full | Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis |
title_fullStr | Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis |
title_full_unstemmed | Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis |
title_short | Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis |
title_sort | efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169517/ https://www.ncbi.nlm.nih.gov/pubmed/21931544 http://dx.doi.org/10.1371/journal.pcbi.1002149 |
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