Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice
Abstract Niemann-Pick disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease. NPC1-patients suffer, amongst others, from ataxia, based on a loss of cerebellar Purkinje cells (PCs). Impaired expression/function of excitatory amino acid transporters (EAATs) are suspected of contributing...
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2018-02-01
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Online Access: | https://doi.org/10.1038/s41598-018-21805-z |
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doaj-8a7a8cdad48c4320bb1096a908cfd2a02020-12-08T05:05:11ZengNature Publishing GroupScientific Reports2045-23222018-02-01811910.1038/s41598-018-21805-zImpact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient MiceMichael Rabenstein0Franziska Peter1Arndt Rolfs2Moritz J. Frech3Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine RostockAlbrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine RostockAlbrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine RostockAlbrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine RostockAbstract Niemann-Pick disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease. NPC1-patients suffer, amongst others, from ataxia, based on a loss of cerebellar Purkinje cells (PCs). Impaired expression/function of excitatory amino acid transporters (EAATs) are suspected of contributing to PC-degeneration in hereditary spinocerebellar ataxias (SCAs). Thus, we studied EAAT-expression and its impact to PC-activity in NPC1−/–mice. Western blot revealed reduced EAAT1, EAAT2, EAAT4, and βIII-spectrin levels in NPC1−/–mice. EAATs play a crucial role in synaptic transmission, thus we were interested in the impact of the reduced EAAT-expression on the function of PCs. Patch-clamp recordings of PCs showed no differences in the firing patterns of NPC1+/+and NPC1−/–mice using a low internal chloride concentration. Because EAAT4 also comprises a chloride permeable ion pore, we perturbed the chloride homeostasis using a high internal chloride concentration. We observed differences in the firing patterns of NPC1+/+and NPC1−/–mice, suggesting an impact of the altered EAAT4-expression. Additionally, the EAAT-antagonist DL-TBOA acts differently in NPC1+/+and NPC1−/–mice. Our data support the line of evidence that an altered EAAT-expression/function is involved in neurodegeneration of PCs observed in SCAs. Thus, we suggest that similar pathogenic mechanisms contribute the loss of PCs in NPC1.https://doi.org/10.1038/s41598-018-21805-z |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael Rabenstein Franziska Peter Arndt Rolfs Moritz J. Frech |
spellingShingle |
Michael Rabenstein Franziska Peter Arndt Rolfs Moritz J. Frech Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice Scientific Reports |
author_facet |
Michael Rabenstein Franziska Peter Arndt Rolfs Moritz J. Frech |
author_sort |
Michael Rabenstein |
title |
Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice |
title_short |
Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice |
title_full |
Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice |
title_fullStr |
Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice |
title_full_unstemmed |
Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice |
title_sort |
impact of reduced cerebellar eaat expression on purkinje cell firing pattern of npc1-deficient mice |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2018-02-01 |
description |
Abstract Niemann-Pick disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease. NPC1-patients suffer, amongst others, from ataxia, based on a loss of cerebellar Purkinje cells (PCs). Impaired expression/function of excitatory amino acid transporters (EAATs) are suspected of contributing to PC-degeneration in hereditary spinocerebellar ataxias (SCAs). Thus, we studied EAAT-expression and its impact to PC-activity in NPC1−/–mice. Western blot revealed reduced EAAT1, EAAT2, EAAT4, and βIII-spectrin levels in NPC1−/–mice. EAATs play a crucial role in synaptic transmission, thus we were interested in the impact of the reduced EAAT-expression on the function of PCs. Patch-clamp recordings of PCs showed no differences in the firing patterns of NPC1+/+and NPC1−/–mice using a low internal chloride concentration. Because EAAT4 also comprises a chloride permeable ion pore, we perturbed the chloride homeostasis using a high internal chloride concentration. We observed differences in the firing patterns of NPC1+/+and NPC1−/–mice, suggesting an impact of the altered EAAT4-expression. Additionally, the EAAT-antagonist DL-TBOA acts differently in NPC1+/+and NPC1−/–mice. Our data support the line of evidence that an altered EAAT-expression/function is involved in neurodegeneration of PCs observed in SCAs. Thus, we suggest that similar pathogenic mechanisms contribute the loss of PCs in NPC1. |
url |
https://doi.org/10.1038/s41598-018-21805-z |
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