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A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2
Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in gen...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444899/ https://www.ncbi.nlm.nih.gov/pubmed/28518055 http://dx.doi.org/10.7554/eLife.26377 |
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author | Meera, Pratap Pulst, Stefan Otis, Thomas |
author_facet | Meera, Pratap Pulst, Stefan Otis, Thomas |
author_sort | Meera, Pratap |
collection | PubMed |
description | Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca(2+)] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca(2+)]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2. DOI: http://dx.doi.org/10.7554/eLife.26377.001 |
format | Online Article Text |
id | pubmed-5444899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-54448992017-05-30 A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 Meera, Pratap Pulst, Stefan Otis, Thomas eLife Neuroscience Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca(2+)] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca(2+)]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2. DOI: http://dx.doi.org/10.7554/eLife.26377.001 eLife Sciences Publications, Ltd 2017-05-18 /pmc/articles/PMC5444899/ /pubmed/28518055 http://dx.doi.org/10.7554/eLife.26377 Text en © 2017, Meera et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Meera, Pratap Pulst, Stefan Otis, Thomas A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 |
title | A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 |
title_full | A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 |
title_fullStr | A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 |
title_full_unstemmed | A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 |
title_short | A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 |
title_sort | positive feedback loop linking enhanced mglur function and basal calcium in spinocerebellar ataxia type 2 |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444899/ https://www.ncbi.nlm.nih.gov/pubmed/28518055 http://dx.doi.org/10.7554/eLife.26377 |
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