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Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease
Astroglial dysfunction contributes to the pathogenesis of Huntington’s disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268590/ https://www.ncbi.nlm.nih.gov/pubmed/37279261 http://dx.doi.org/10.1073/pnas.2210719120 |
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author | Villanueva, Carlos Benitez Stephensen, Hans J. T. Mokso, Rajmund Benraiss, Abdellatif Sporring, Jon Goldman, Steven A. |
author_facet | Villanueva, Carlos Benitez Stephensen, Hans J. T. Mokso, Rajmund Benraiss, Abdellatif Sporring, Jon Goldman, Steven A. |
author_sort | Villanueva, Carlos Benitez |
collection | PubMed |
description | Astroglial dysfunction contributes to the pathogenesis of Huntington’s disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of turboRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs in R6/2 HD and wild-type (WT) mice. The tagged, prospectively identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nanometer-scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in the astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K(+) that underlie striatal hyperexcitability in HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation. |
format | Online Article Text |
id | pubmed-10268590 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-102685902023-06-16 Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease Villanueva, Carlos Benitez Stephensen, Hans J. T. Mokso, Rajmund Benraiss, Abdellatif Sporring, Jon Goldman, Steven A. Proc Natl Acad Sci U S A Biological Sciences Astroglial dysfunction contributes to the pathogenesis of Huntington’s disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of turboRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs in R6/2 HD and wild-type (WT) mice. The tagged, prospectively identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nanometer-scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in the astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K(+) that underlie striatal hyperexcitability in HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation. National Academy of Sciences 2023-06-06 2023-06-13 /pmc/articles/PMC10268590/ /pubmed/37279261 http://dx.doi.org/10.1073/pnas.2210719120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Villanueva, Carlos Benitez Stephensen, Hans J. T. Mokso, Rajmund Benraiss, Abdellatif Sporring, Jon Goldman, Steven A. Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease |
title | Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease |
title_full | Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease |
title_fullStr | Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease |
title_full_unstemmed | Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease |
title_short | Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease |
title_sort | astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of huntington’s disease |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268590/ https://www.ncbi.nlm.nih.gov/pubmed/37279261 http://dx.doi.org/10.1073/pnas.2210719120 |
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