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Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca(2+) imagi...

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Autores principales: Arnoux, Isabelle, Willam, Michael, Griesche, Nadine, Krummeich, Jennifer, Watari, Hirofumi, Offermann, Nina, Weber, Stephanie, Narayan Dey, Partha, Chen, Changwei, Monteiro, Olivia, Buettner, Sven, Meyer, Katharina, Bano, Daniele, Radyushkin, Konstantin, Langston, Rosamund, Lambert, Jeremy J, Wanker, Erich, Methner, Axel, Krauss, Sybille, Schweiger, Susann, Stroh, Albrecht
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156080/
https://www.ncbi.nlm.nih.gov/pubmed/30179155
http://dx.doi.org/10.7554/eLife.38744
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author Arnoux, Isabelle
Willam, Michael
Griesche, Nadine
Krummeich, Jennifer
Watari, Hirofumi
Offermann, Nina
Weber, Stephanie
Narayan Dey, Partha
Chen, Changwei
Monteiro, Olivia
Buettner, Sven
Meyer, Katharina
Bano, Daniele
Radyushkin, Konstantin
Langston, Rosamund
Lambert, Jeremy J
Wanker, Erich
Methner, Axel
Krauss, Sybille
Schweiger, Susann
Stroh, Albrecht
author_facet Arnoux, Isabelle
Willam, Michael
Griesche, Nadine
Krummeich, Jennifer
Watari, Hirofumi
Offermann, Nina
Weber, Stephanie
Narayan Dey, Partha
Chen, Changwei
Monteiro, Olivia
Buettner, Sven
Meyer, Katharina
Bano, Daniele
Radyushkin, Konstantin
Langston, Rosamund
Lambert, Jeremy J
Wanker, Erich
Methner, Axel
Krauss, Sybille
Schweiger, Susann
Stroh, Albrecht
author_sort Arnoux, Isabelle
collection PubMed
description Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca(2+) imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms.
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spelling pubmed-61560802018-09-25 Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease Arnoux, Isabelle Willam, Michael Griesche, Nadine Krummeich, Jennifer Watari, Hirofumi Offermann, Nina Weber, Stephanie Narayan Dey, Partha Chen, Changwei Monteiro, Olivia Buettner, Sven Meyer, Katharina Bano, Daniele Radyushkin, Konstantin Langston, Rosamund Lambert, Jeremy J Wanker, Erich Methner, Axel Krauss, Sybille Schweiger, Susann Stroh, Albrecht eLife Neuroscience Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca(2+) imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms. eLife Sciences Publications, Ltd 2018-09-04 /pmc/articles/PMC6156080/ /pubmed/30179155 http://dx.doi.org/10.7554/eLife.38744 Text en © 2018, Arnoux et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Arnoux, Isabelle
Willam, Michael
Griesche, Nadine
Krummeich, Jennifer
Watari, Hirofumi
Offermann, Nina
Weber, Stephanie
Narayan Dey, Partha
Chen, Changwei
Monteiro, Olivia
Buettner, Sven
Meyer, Katharina
Bano, Daniele
Radyushkin, Konstantin
Langston, Rosamund
Lambert, Jeremy J
Wanker, Erich
Methner, Axel
Krauss, Sybille
Schweiger, Susann
Stroh, Albrecht
Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
title Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
title_full Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
title_fullStr Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
title_full_unstemmed Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
title_short Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
title_sort metformin reverses early cortical network dysfunction and behavior changes in huntington’s disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156080/
https://www.ncbi.nlm.nih.gov/pubmed/30179155
http://dx.doi.org/10.7554/eLife.38744
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