Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia
Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rode...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823001299 |
| _version_ | 1828716505850707968 |
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| author | Shu-Tao Xie Wen-Chu Fan Xian-Sen Zhao Xiao-Yang Ma Ze-Lin Li Yan-Ran Zhao Fa Yang Ying Shi Hui Rong Zhi-San Cui Jun-Yi Chen Hong-Zhao Li Chao Yan Qipeng Zhang Jian-Jun Wang Xiao-Yang Zhang Xiao-Ping Gu Zheng-Liang Ma Jing-Ning Zhu |
| author_facet | Shu-Tao Xie Wen-Chu Fan Xian-Sen Zhao Xiao-Yang Ma Ze-Lin Li Yan-Ran Zhao Fa Yang Ying Shi Hui Rong Zhi-San Cui Jun-Yi Chen Hong-Zhao Li Chao Yan Qipeng Zhang Jian-Jun Wang Xiao-Yang Zhang Xiao-Ping Gu Zheng-Liang Ma Jing-Ning Zhu |
| author_sort | Shu-Tao Xie |
| collection | DOAJ |
| description | Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators. |
| first_indexed | 2024-03-12T14:13:25Z |
| format | Article |
| id | doaj.art-2f79829d96be4152986eec42f91a357e |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-12T14:13:25Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-2f79829d96be4152986eec42f91a357e2023-08-21T04:19:56ZengElsevierPharmacological Research1096-11862023-05-01191106773Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxiaShu-Tao Xie0Wen-Chu Fan1Xian-Sen Zhao2Xiao-Yang Ma3Ze-Lin Li4Yan-Ran Zhao5Fa Yang6Ying Shi7Hui Rong8Zhi-San Cui9Jun-Yi Chen10Hong-Zhao Li11Chao Yan12Qipeng Zhang13Jian-Jun Wang14Xiao-Yang Zhang15Xiao-Ping Gu16Zheng-Liang Ma17Jing-Ning Zhu18State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Institute for Brain Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Institute for Brain Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Institute for Brain Sciences, Nanjing University, Nanjing, China; Corresponding authors at: State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Institute for Brain Sciences, Nanjing University, Nanjing, China; Corresponding authors at: State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Institute for Brain Sciences, Nanjing University, Nanjing, China; Corresponding authors at: State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Institute for Brain Sciences, Nanjing University, Nanjing, China; Corresponding authors at: State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, and Department of Anesthesiology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, ChinaSpecific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.http://www.sciencedirect.com/science/article/pii/S1043661823001299CerebellumMicrogliaChemogenetic manipulationPurkinje cellAtaxia |
| spellingShingle | Shu-Tao Xie Wen-Chu Fan Xian-Sen Zhao Xiao-Yang Ma Ze-Lin Li Yan-Ran Zhao Fa Yang Ying Shi Hui Rong Zhi-San Cui Jun-Yi Chen Hong-Zhao Li Chao Yan Qipeng Zhang Jian-Jun Wang Xiao-Yang Zhang Xiao-Ping Gu Zheng-Liang Ma Jing-Ning Zhu Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia Pharmacological Research Cerebellum Microglia Chemogenetic manipulation Purkinje cell Ataxia |
| title | Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia |
| title_full | Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia |
| title_fullStr | Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia |
| title_full_unstemmed | Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia |
| title_short | Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia |
| title_sort | proinflammatory activation of microglia in the cerebellum hyperexcites purkinje cells to trigger ataxia |
| topic | Cerebellum Microglia Chemogenetic manipulation Purkinje cell Ataxia |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823001299 |
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