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Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice
Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in huntingtin. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology are not fully understood. Here, using a male zQ...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011605/ https://www.ncbi.nlm.nih.gov/pubmed/36914640 http://dx.doi.org/10.1038/s41467-023-36556-3 |
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author | Pancani, Tristano Day, Michelle Tkatch, Tatiana Wokosin, David L. González-Rodríguez, Patricia Kondapalli, Jyothisri Xie, Zhong Chen, Yu Beaumont, Vahri Surmeier, D. James |
author_facet | Pancani, Tristano Day, Michelle Tkatch, Tatiana Wokosin, David L. González-Rodríguez, Patricia Kondapalli, Jyothisri Xie, Zhong Chen, Yu Beaumont, Vahri Surmeier, D. James |
author_sort | Pancani, Tristano |
collection | PubMed |
description | Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in huntingtin. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology are not fully understood. Here, using a male zQ175(+/−) knock-in mouse model of HD we carry out optogenetic interrogation of intratelencephalic and pyramidal tract synapses with principal striatal spiny projection neurons (SPNs). These studies reveal that the connectivity of intratelencephalic, but not pyramidal tract, neurons with direct and indirect pathway SPNs increased in early symptomatic zQ175(+/−) HD mice. This enhancement was attributable to reduced pre-synaptic inhibitory control of intratelencephalic terminals by striatal cholinergic interneurons. Lowering mutant huntingtin selectively in striatal cholinergic interneurons with a virally-delivered zinc finger repressor protein normalized striatal acetylcholine release and intratelencephalic functional connectivity, revealing a node in the network underlying corticostriatal pathophysiology in a HD mouse model. |
format | Online Article Text |
id | pubmed-10011605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100116052023-03-15 Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice Pancani, Tristano Day, Michelle Tkatch, Tatiana Wokosin, David L. González-Rodríguez, Patricia Kondapalli, Jyothisri Xie, Zhong Chen, Yu Beaumont, Vahri Surmeier, D. James Nat Commun Article Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in huntingtin. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology are not fully understood. Here, using a male zQ175(+/−) knock-in mouse model of HD we carry out optogenetic interrogation of intratelencephalic and pyramidal tract synapses with principal striatal spiny projection neurons (SPNs). These studies reveal that the connectivity of intratelencephalic, but not pyramidal tract, neurons with direct and indirect pathway SPNs increased in early symptomatic zQ175(+/−) HD mice. This enhancement was attributable to reduced pre-synaptic inhibitory control of intratelencephalic terminals by striatal cholinergic interneurons. Lowering mutant huntingtin selectively in striatal cholinergic interneurons with a virally-delivered zinc finger repressor protein normalized striatal acetylcholine release and intratelencephalic functional connectivity, revealing a node in the network underlying corticostriatal pathophysiology in a HD mouse model. Nature Publishing Group UK 2023-03-14 /pmc/articles/PMC10011605/ /pubmed/36914640 http://dx.doi.org/10.1038/s41467-023-36556-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Pancani, Tristano Day, Michelle Tkatch, Tatiana Wokosin, David L. González-Rodríguez, Patricia Kondapalli, Jyothisri Xie, Zhong Chen, Yu Beaumont, Vahri Surmeier, D. James Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice |
title | Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice |
title_full | Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice |
title_fullStr | Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice |
title_full_unstemmed | Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice |
title_short | Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice |
title_sort | cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male huntington’s disease model mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011605/ https://www.ncbi.nlm.nih.gov/pubmed/36914640 http://dx.doi.org/10.1038/s41467-023-36556-3 |
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