Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease

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Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease

Henningsen, Jo B (author): Lund University,Lunds universitet,Translationell neuroendokrinologi,Forskargrupper vid Lunds universitet,Translational Neuroendocrinology,Lund University Research Groups,University of Copenhagen

Soylu-Kucharz, Rana (author): Lund University,Lunds universitet,Biomarkörer vid hjärnsjukdomar,Forskargrupper vid Lunds universitet,Translationell neuroendokrinologi,Biomarkers in Brain Disease,Lund University Research Groups,Translational Neuroendocrinology

Björkqvist, Maria (author): Lund University,Lunds universitet,Biomarkörer vid hjärnsjukdomar,Forskargrupper vid Lunds universitet,Biomarkers in Brain Disease,Lund University Research Groups

Petersén, Åsa (author): Lund University,Lunds universitet,Translationell neuroendokrinologi,Forskargrupper vid Lunds universitet,Translational Neuroendocrinology,Lund University Research Groups

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Elsevier BV, 2021
2021
English.
In: Heliyon. - : Elsevier BV. - 2405-8440. ; 7:8, s. 1-9

Related links:: http://dx.doi.org/10... (free); show more...; http://www.cell.com/...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)

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By the author/editor: Henningsen, Jo B; Soylu-Kucharz, R ...; Björkqvist, Mari ...; Petersén, Åsa

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

Articles in the publication: Heliyon

By the university: Lund University

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