Frontiers in Cellular Neuroscience (Jun 2020)
Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease
- 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
Affiliations
- Anya Kim
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Anya Kim
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Anya Kim
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Anya Kim
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Esther García-García
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Esther García-García
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Esther García-García
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Esther García-García
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Marco Straccia
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Marco Straccia
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Marco Straccia
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Marco Straccia
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Marco Straccia
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Andrea Comella-Bolla
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Andrea Comella-Bolla
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Andrea Comella-Bolla
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Andrea Comella-Bolla
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Andrea Comella-Bolla
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Andrés Miguez
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Andrés Miguez
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Andrés Miguez
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Andrés Miguez
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Andrés Miguez
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Mercè Masana
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Mercè Masana
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Mercè Masana
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Mercè Masana
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Jordi Alberch
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Jordi Alberch
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Jordi Alberch
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Jordi Alberch
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Jordi Alberch
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Josep M. Canals
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Josep M. Canals
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Josep M. Canals
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- Josep M. Canals
- Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Josep M. Canals
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
- Manuel J. Rodríguez
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Manuel J. Rodríguez
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- Manuel J. Rodríguez
- August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- Manuel J. Rodríguez
- Network Center for Biomedical Research in Neurodegenerative Diseases, Barcelona, Spain
- DOI
- https://doi.org/10.3389/fncel.2020.00163
- Journal volume & issue
-
Vol. 14
Abstract
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.
Keywords
