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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...

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Autores principales: Villanueva, Carlos Benitez, Stephensen, Hans J. T., Mokso, Rajmund, Benraiss, Abdellatif, Sporring, Jon, Goldman, Steven A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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