Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease
Huntington’s disease (HD) is an inherited neurodegenerative disorder in which the striatum is the most affected brain region. Although a chronic inflammatory microglial reaction that amplifies disease progression has been described in HD patients, some murine models develop symptoms without inflamma...
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| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2020.00163/full |
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| author | Anya Kim Anya Kim Anya Kim Anya Kim Esther García-García Esther García-García Esther García-García Esther García-García Marco Straccia Marco Straccia Marco Straccia Marco Straccia Marco Straccia Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrés Miguez Andrés Miguez Andrés Miguez Andrés Miguez Andrés Miguez Mercè Masana Mercè Masana Mercè Masana Mercè Masana Jordi Alberch Jordi Alberch Jordi Alberch Jordi Alberch Jordi Alberch Josep M. Canals Josep M. Canals Josep M. Canals Josep M. Canals Josep M. Canals Manuel J. Rodríguez Manuel J. Rodríguez Manuel J. Rodríguez Manuel J. Rodríguez |
| author_facet | Anya Kim Anya Kim Anya Kim Anya Kim Esther García-García Esther García-García Esther García-García Esther García-García Marco Straccia Marco Straccia Marco Straccia Marco Straccia Marco Straccia Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrés Miguez Andrés Miguez Andrés Miguez Andrés Miguez Andrés Miguez Mercè Masana Mercè Masana Mercè Masana Mercè Masana Jordi Alberch Jordi Alberch Jordi Alberch Jordi Alberch Jordi Alberch Josep M. Canals Josep M. Canals Josep M. Canals Josep M. Canals Josep M. Canals Manuel J. Rodríguez Manuel J. Rodríguez Manuel J. Rodríguez Manuel J. Rodríguez |
| author_sort | Anya Kim |
| collection | DOAJ |
| description | Huntington’s disease (HD) is an inherited neurodegenerative disorder in which the striatum is the most affected brain region. Although a chronic inflammatory microglial reaction that amplifies disease progression has been described in HD patients, some murine models develop symptoms without inflammatory microglial activation. Thus, dysfunction of non-inflammatory microglial activity could also contribute to the early HD pathological process. Here, we show the involvement of microglia and particularly fractalkine signaling in the striatal synaptic dysfunction of R6/1 mice. We found reduced fractalkine gene expression and protein concentration in R6/1 striata from 8 to 20 weeks of age. Consistently, we also observed a down-regulation of fractalkine levels in the putamen of HD patients and in HD patient hiPSC-derived neurons. Automated cell morphology analysis showed a non-inflammatory ramified microglia in the striatum of R6/1 mice. However, we found increased PSD-95-positive puncta inside microglia, indicative of synaptic pruning, before HD motor symptoms start to manifest. Indeed, microglia appeared to be essential for striatal synaptic function, as the inhibition of microglial activity with minocycline impaired the induction of corticostriatal long-term depression (LTD) in wild-type mice. Notably, fractalkine administration restored impaired corticostriatal LTD in R6/1 mice. Our results unveil a role for fractalkine-dependent neuron-microglia interactions in the early striatal synaptic dysfunction characteristic of HD. |
| first_indexed | 2024-12-23T10:34:33Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-23T10:34:33Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-1f4979cb7658431c9570c1e7abeb289a2022-12-21T17:50:20ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-06-011410.3389/fncel.2020.00163546733Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s DiseaseAnya Kim0Anya Kim1Anya Kim2Anya Kim3Esther García-García4Esther García-García5Esther García-García6Esther García-García7Marco Straccia8Marco Straccia9Marco Straccia10Marco Straccia11Marco Straccia12Andrea Comella-Bolla13Andrea Comella-Bolla14Andrea Comella-Bolla15Andrea Comella-Bolla16Andrea Comella-Bolla17Andrés Miguez18Andrés Miguez19Andrés Miguez20Andrés Miguez21Andrés Miguez22Mercè Masana23Mercè Masana24Mercè Masana25Mercè Masana26Jordi Alberch27Jordi Alberch28Jordi Alberch29Jordi Alberch30Jordi Alberch31Josep M. Canals32Josep M. Canals33Josep M. Canals34Josep M. Canals35Josep M. Canals36Manuel J. Rodríguez37Manuel J. Rodríguez38Manuel J. Rodríguez39Manuel J. Rodríguez40Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainLaboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainProduction and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainLaboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainProduction and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainLaboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainProduction and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainLaboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainLaboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainProduction and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, SpainDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, SpainInstitute of Neurosciences, University of Barcelona, Barcelona, SpainAugust Pi i Sunyer Biomedical Research Institute, Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, SpainHuntington’s disease (HD) is an inherited neurodegenerative disorder in which the striatum is the most affected brain region. Although a chronic inflammatory microglial reaction that amplifies disease progression has been described in HD patients, some murine models develop symptoms without inflammatory microglial activation. Thus, dysfunction of non-inflammatory microglial activity could also contribute to the early HD pathological process. Here, we show the involvement of microglia and particularly fractalkine signaling in the striatal synaptic dysfunction of R6/1 mice. We found reduced fractalkine gene expression and protein concentration in R6/1 striata from 8 to 20 weeks of age. Consistently, we also observed a down-regulation of fractalkine levels in the putamen of HD patients and in HD patient hiPSC-derived neurons. Automated cell morphology analysis showed a non-inflammatory ramified microglia in the striatum of R6/1 mice. However, we found increased PSD-95-positive puncta inside microglia, indicative of synaptic pruning, before HD motor symptoms start to manifest. Indeed, microglia appeared to be essential for striatal synaptic function, as the inhibition of microglial activity with minocycline impaired the induction of corticostriatal long-term depression (LTD) in wild-type mice. Notably, fractalkine administration restored impaired corticostriatal LTD in R6/1 mice. Our results unveil a role for fractalkine-dependent neuron-microglia interactions in the early striatal synaptic dysfunction characteristic of HD.https://www.frontiersin.org/article/10.3389/fncel.2020.00163/fullhuntingtinCX3CL1microgliacorticostriatal pathwaysynaptic pruninghuman iPSC |
| spellingShingle | Anya Kim Anya Kim Anya Kim Anya Kim Esther García-García Esther García-García Esther García-García Esther García-García Marco Straccia Marco Straccia Marco Straccia Marco Straccia Marco Straccia Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrea Comella-Bolla Andrés Miguez Andrés Miguez Andrés Miguez Andrés Miguez Andrés Miguez Mercè Masana Mercè Masana Mercè Masana Mercè Masana Jordi Alberch Jordi Alberch Jordi Alberch Jordi Alberch Jordi Alberch Josep M. Canals Josep M. Canals Josep M. Canals Josep M. Canals Josep M. Canals Manuel J. Rodríguez Manuel J. Rodríguez Manuel J. Rodríguez Manuel J. Rodríguez Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease Frontiers in Cellular Neuroscience huntingtin CX3CL1 microglia corticostriatal pathway synaptic pruning human iPSC |
| title | Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease |
| title_full | Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease |
| title_fullStr | Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease |
| title_full_unstemmed | Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease |
| title_short | Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease |
| title_sort | reduced fractalkine levels lead to striatal synaptic plasticity deficits in huntington s disease |
| topic | huntingtin CX3CL1 microglia corticostriatal pathway synaptic pruning human iPSC |
| url | https://www.frontiersin.org/article/10.3389/fncel.2020.00163/full |
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