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Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression
Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9445039/ https://www.ncbi.nlm.nih.gov/pubmed/36064798 http://dx.doi.org/10.1038/s41536-022-00243-6 |
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author | Asthana, Pallavi Kumar, Gajendra Milanowski, Lukasz M. Au, Ngan Pan Bennett Chan, Siu Chung Huang, Jianpan Feng, Hemin Kwan, Kin Ming He, Jufang Chan, Kannie Wai Yan Wszolek, Zbigniew K. Ma, Chi Him Eddie |
author_facet | Asthana, Pallavi Kumar, Gajendra Milanowski, Lukasz M. Au, Ngan Pan Bennett Chan, Siu Chung Huang, Jianpan Feng, Hemin Kwan, Kin Ming He, Jufang Chan, Kannie Wai Yan Wszolek, Zbigniew K. Ma, Chi Him Eddie |
author_sort | Asthana, Pallavi |
collection | PubMed |
description | Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI. |
format | Online Article Text |
id | pubmed-9445039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94450392022-09-07 Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression Asthana, Pallavi Kumar, Gajendra Milanowski, Lukasz M. Au, Ngan Pan Bennett Chan, Siu Chung Huang, Jianpan Feng, Hemin Kwan, Kin Ming He, Jufang Chan, Kannie Wai Yan Wszolek, Zbigniew K. Ma, Chi Him Eddie NPJ Regen Med Article Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI. Nature Publishing Group UK 2022-09-05 /pmc/articles/PMC9445039/ /pubmed/36064798 http://dx.doi.org/10.1038/s41536-022-00243-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Asthana, Pallavi Kumar, Gajendra Milanowski, Lukasz M. Au, Ngan Pan Bennett Chan, Siu Chung Huang, Jianpan Feng, Hemin Kwan, Kin Ming He, Jufang Chan, Kannie Wai Yan Wszolek, Zbigniew K. Ma, Chi Him Eddie Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression |
title | Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression |
title_full | Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression |
title_fullStr | Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression |
title_full_unstemmed | Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression |
title_short | Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression |
title_sort | cerebellar glutamatergic system impacts spontaneous motor recovery by regulating gria1 expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9445039/ https://www.ncbi.nlm.nih.gov/pubmed/36064798 http://dx.doi.org/10.1038/s41536-022-00243-6 |
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