Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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
_version_ 1784783340500418560
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
work_keys_str_mv AT asthanapallavi cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT kumargajendra cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT milanowskilukaszm cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT aunganpanbennett cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT chansiuchung cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT huangjianpan cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT fenghemin cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT kwankinming cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT hejufang cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT chankanniewaiyan cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT wszolekzbigniewk cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression
AT machihimeddie cerebellarglutamatergicsystemimpactsspontaneousmotorrecoverybyregulatinggria1expression