GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context
Background: Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods: Biochemical and electrophysiological methods were used to assess...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418305437 |
| _version_ | 1811262748933226496 |
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| author | Malgorzata Urbanska Paulina Kazmierska-Grebowska Tomasz Kowalczyk Bartosz Caban Karolina Nader Barbara Pijet Katarzyna Kalita Agata Gozdz Herman Devijver Benoit Lechat Tomasz Jaworski Wieslawa Grajkowska Krzysztof Sadowski Sergiusz Jozwiak Katarzyna Kotulska Jan Konopacki Fred Van Leuven Erwin A. van Vliet Eleonora Aronica Jacek Jaworski |
| author_facet | Malgorzata Urbanska Paulina Kazmierska-Grebowska Tomasz Kowalczyk Bartosz Caban Karolina Nader Barbara Pijet Katarzyna Kalita Agata Gozdz Herman Devijver Benoit Lechat Tomasz Jaworski Wieslawa Grajkowska Krzysztof Sadowski Sergiusz Jozwiak Katarzyna Kotulska Jan Konopacki Fred Van Leuven Erwin A. van Vliet Eleonora Aronica Jacek Jaworski |
| author_sort | Malgorzata Urbanska |
| collection | DOAJ |
| description | Background: Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods: Biochemical and electrophysiological methods were used to assess the role of GSK3β in regulating neuronal transmission and epileptogenesis. GSK3β activity was increased genetically in GSK3β[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3β phosphorylation. Findings: Higher GSK3β activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3β activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 under basal conditions and in the epileptic mouse brain and decreased phosphorylation of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 at Serine 831 under basal conditions. Moreover, we found a significant correlation between higher inhibitory GSK3β phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. Interpretation: Our data imply GSK3β activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3β involves modulation of HCN4 level and the synaptic AMPA receptors pool. Keywords: Glycogen synthase kinases-3, GSK3, Epilepsy, AMPA receptors, GluA1 phosphorylation |
| first_indexed | 2024-04-12T19:31:01Z |
| format | Article |
| id | doaj.art-ccb24ce7f72a4cd2a2d94b67aaf14db7 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-12T19:31:01Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-ccb24ce7f72a4cd2a2d94b67aaf14db72022-12-22T03:19:20ZengElsevierEBioMedicine2352-39642019-01-0139377387GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in contextMalgorzata Urbanska0Paulina Kazmierska-Grebowska1Tomasz Kowalczyk2Bartosz Caban3Karolina Nader4Barbara Pijet5Katarzyna Kalita6Agata Gozdz7Herman Devijver8Benoit Lechat9Tomasz Jaworski10Wieslawa Grajkowska11Krzysztof Sadowski12Sergiusz Jozwiak13Katarzyna Kotulska14Jan Konopacki15Fred Van Leuven16Erwin A. van Vliet17Eleonora Aronica18Jacek Jaworski19Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland; Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-730, Poland; Correspondence to: M. Urbanska, Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Ks. Trojdena St. 4, Warsaw 02-109, Poland.Department of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, PolandDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, PolandDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw 02-093, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw 02-093, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw 02-093, PolandLaboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw 02-109, PolandExperimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven 3000, BelgiumExperimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven 3000, BelgiumLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw 02-093, PolandDepartment of Pathology, Children's Memorial Health Institute, Warsaw 04-730, PolandDepartment of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-730, PolandDepartment of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-730, Poland; Department of Child Neurology, Medical University of Warsaw, Warsaw 02-091, PolandDepartment of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-730, PolandDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, PolandExperimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven 3000, BelgiumAmsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, 1098 XH, the NetherlandsAmsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, Amsterdam Neuroscience, Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the NetherlandsLaboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland; Correspondence to: J. Jaworski, Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Ks. Trojdena St. 4, Warsaw 02-109,Poland.Background: Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods: Biochemical and electrophysiological methods were used to assess the role of GSK3β in regulating neuronal transmission and epileptogenesis. GSK3β activity was increased genetically in GSK3β[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3β phosphorylation. Findings: Higher GSK3β activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3β activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 under basal conditions and in the epileptic mouse brain and decreased phosphorylation of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 at Serine 831 under basal conditions. Moreover, we found a significant correlation between higher inhibitory GSK3β phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. Interpretation: Our data imply GSK3β activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3β involves modulation of HCN4 level and the synaptic AMPA receptors pool. Keywords: Glycogen synthase kinases-3, GSK3, Epilepsy, AMPA receptors, GluA1 phosphorylationhttp://www.sciencedirect.com/science/article/pii/S2352396418305437 |
| spellingShingle | Malgorzata Urbanska Paulina Kazmierska-Grebowska Tomasz Kowalczyk Bartosz Caban Karolina Nader Barbara Pijet Katarzyna Kalita Agata Gozdz Herman Devijver Benoit Lechat Tomasz Jaworski Wieslawa Grajkowska Krzysztof Sadowski Sergiusz Jozwiak Katarzyna Kotulska Jan Konopacki Fred Van Leuven Erwin A. van Vliet Eleonora Aronica Jacek Jaworski GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context EBioMedicine |
| title | GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context |
| title_full | GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context |
| title_fullStr | GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context |
| title_full_unstemmed | GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context |
| title_short | GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context |
| title_sort | gsk3β activity alleviates epileptogenesis and limits glua1 phosphorylationresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418305437 |
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