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Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease
Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology w...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379469/ https://www.ncbi.nlm.nih.gov/pubmed/34458633 http://dx.doi.org/10.1016/j.heliyon.2021.e07808 |
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author | Henningsen, Jo B. Soylu-Kucharz, Rana Björkqvist, Maria Petersén, Åsa |
author_facet | Henningsen, Jo B. Soylu-Kucharz, Rana Björkqvist, Maria Petersén, Åsa |
author_sort | Henningsen, Jo B. |
collection | PubMed |
description | Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD. |
format | Online Article Text |
id | pubmed-8379469 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-83794692021-08-26 Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease Henningsen, Jo B. Soylu-Kucharz, Rana Björkqvist, Maria Petersén, Åsa Heliyon Research Article Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD. Elsevier 2021-08-14 /pmc/articles/PMC8379469/ /pubmed/34458633 http://dx.doi.org/10.1016/j.heliyon.2021.e07808 Text en © 2021 Published by Elsevier Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Henningsen, Jo B. Soylu-Kucharz, Rana Björkqvist, Maria Petersén, Åsa Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease |
title | Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease |
title_full | Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease |
title_fullStr | Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease |
title_full_unstemmed | Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease |
title_short | Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease |
title_sort | effects of excitotoxicity in the hypothalamus in transgenic mouse models of huntington disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379469/ https://www.ncbi.nlm.nih.gov/pubmed/34458633 http://dx.doi.org/10.1016/j.heliyon.2021.e07808 |
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