Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex
Extracellular potassium concentration, [K+]o, is a major determinant of neuronal excitability. In the healthy brain, [K+]o levels are tightly controlled. During seizures, [K+]o increases up to 15 mM and is thought to cause seizures due to its depolarizing effect. Although astrocytes have been sugges...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-05-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116302984 |
| _version_ | 1818352024075370496 |
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| author | Paolo Bazzigaluppi Iliya Weisspapir Bojana Stefanovic Luc Leybaert Peter L. Carlen |
| author_facet | Paolo Bazzigaluppi Iliya Weisspapir Bojana Stefanovic Luc Leybaert Peter L. Carlen |
| author_sort | Paolo Bazzigaluppi |
| collection | DOAJ |
| description | Extracellular potassium concentration, [K+]o, is a major determinant of neuronal excitability. In the healthy brain, [K+]o levels are tightly controlled. During seizures, [K+]o increases up to 15 mM and is thought to cause seizures due to its depolarizing effect. Although astrocytes have been suggested to play a key role in the redistribution (or spatial buffering) of excess K+ through Connexin-43 (Cx43)-based Gap Junctions (GJs), the relation between this dynamic regulatory process and seizure generation remains unknown. Here we contrasted the role of astrocytic GJs and hemichannels by studying the effect of GJ and hemichannel blockers on [K+]o regulation in vivo. [K+]o was measured by K+-sensitive microelectrodes. Neuronal excitability was estimated by local field potential (LFP) responses to forepaw stimulation and changes in the power of resting state activity. Starting at the baseline [K+]o level of 1.61 ± 0.3 mM, cortical microinjection of CBX, a broad spectrum connexin channel blocker, increased [K+]o to 11 ± 3 mM, Cx43 GJ/hemichannel blocker Gap27 increased it from 1.9 ± 0.7 to 9 ± 1 mM. At these [K+]o levels, no seizures were observed. Cx43 hemichannel blockade with TAT-Gap19 increased [K+]o by only ~1 mM. Microinjection of 4-aminopyridine, a known convulsant, increased [K+]o to ~10 mM and induced spontaneously recurring seizures, whereas direct application of K+ did not trigger seizure activity. These findings are the first in vivo demonstration that astrocytic GJs are major determinants for the spatial buffering of [K+]o and that an increase in [K+]o alone does not trigger seizures in the neocortex. |
| first_indexed | 2024-12-13T18:47:03Z |
| format | Article |
| id | doaj.art-32490f6174674eb2ad74eb9da31f6920 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:47:03Z |
| publishDate | 2017-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-32490f6174674eb2ad74eb9da31f69202022-12-21T23:35:02ZengElsevierNeurobiology of Disease1095-953X2017-05-0110117Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortexPaolo Bazzigaluppi0Iliya Weisspapir1Bojana Stefanovic2Luc Leybaert3Peter L. Carlen4Fundamental Neurobiology, Krembil Research Institute, University Health Network, M5T 2S8 Toronto, Ontario, Canada; Physical Sciences, Sunnybrook Research Institute, M4N 3M5 Toronto, Ontario, Canada; Corresponding author at: Krembil Research Institute, University Health Network, 7KDT 430, 60 Leonard Av., M5T 2S8 Toronto, Ontario, Canada.Fundamental Neurobiology, Krembil Research Institute, University Health Network, M5T 2S8 Toronto, Ontario, CanadaPhysical Sciences, Sunnybrook Research Institute, M4N 3M5 Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Ontario, CanadaDepartment of Basic Medical Sciences, University of Ghent, 9000 Ghent, BelgiumFundamental Neurobiology, Krembil Research Institute, University Health Network, M5T 2S8 Toronto, Ontario, CanadaExtracellular potassium concentration, [K+]o, is a major determinant of neuronal excitability. In the healthy brain, [K+]o levels are tightly controlled. During seizures, [K+]o increases up to 15 mM and is thought to cause seizures due to its depolarizing effect. Although astrocytes have been suggested to play a key role in the redistribution (or spatial buffering) of excess K+ through Connexin-43 (Cx43)-based Gap Junctions (GJs), the relation between this dynamic regulatory process and seizure generation remains unknown. Here we contrasted the role of astrocytic GJs and hemichannels by studying the effect of GJ and hemichannel blockers on [K+]o regulation in vivo. [K+]o was measured by K+-sensitive microelectrodes. Neuronal excitability was estimated by local field potential (LFP) responses to forepaw stimulation and changes in the power of resting state activity. Starting at the baseline [K+]o level of 1.61 ± 0.3 mM, cortical microinjection of CBX, a broad spectrum connexin channel blocker, increased [K+]o to 11 ± 3 mM, Cx43 GJ/hemichannel blocker Gap27 increased it from 1.9 ± 0.7 to 9 ± 1 mM. At these [K+]o levels, no seizures were observed. Cx43 hemichannel blockade with TAT-Gap19 increased [K+]o by only ~1 mM. Microinjection of 4-aminopyridine, a known convulsant, increased [K+]o to ~10 mM and induced spontaneously recurring seizures, whereas direct application of K+ did not trigger seizure activity. These findings are the first in vivo demonstration that astrocytic GJs are major determinants for the spatial buffering of [K+]o and that an increase in [K+]o alone does not trigger seizures in the neocortex.http://www.sciencedirect.com/science/article/pii/S0969996116302984Extracellular potassiumGAP27TAT-GAP194-APin vivoSeizures |
| spellingShingle | Paolo Bazzigaluppi Iliya Weisspapir Bojana Stefanovic Luc Leybaert Peter L. Carlen Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex Neurobiology of Disease Extracellular potassium GAP27 TAT-GAP19 4-AP in vivo Seizures |
| title | Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex |
| title_full | Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex |
| title_fullStr | Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex |
| title_full_unstemmed | Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex |
| title_short | Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex |
| title_sort | astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex |
| topic | Extracellular potassium GAP27 TAT-GAP19 4-AP in vivo Seizures |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116302984 |
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