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

Isabelle Arnoux, Michael Willam, Nadine Griesche, Jennifer Krummeich, Hirofumi Watari, Nina Offermann, Stephanie Weber, Partha Narayan Dey, Changwei Chen, Olivia Monteiro, Sven Buettner, Katharina Meyer, Daniele Bano, Konstantin Radyushkin, Rosamund Langston, Jeremy J. Lambert, Erich Wanker, Axel Methner, Sybille Krauss, Susann Schweiger (Lead / Corresponding author)Albrecht Stroh

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Abstract

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 Ca2+ 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 anti-diabetic 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.

Original languageEnglish
Article numbere38744
Pages (from-to)1-32
Number of pages32
JournaleLife
Volume7
DOIs
Publication statusPublished - 4 Sep 2018

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Metformin
Huntington Disease
Animal Behavior
Aberrations
Visual Cortex
Photons
Neurons
Therapeutics
Animals
Pharmaceutical Preparations
Imaging techniques
Networks (circuits)
Proteins

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Arnoux, I., Willam, M., Griesche, N., Krummeich, J., Watari, H., Offermann, N., ... Stroh, A. (2018). Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. eLife, 7, 1-32. [e38744]. https://doi.org/10.7554/eLife.38744
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. In: eLife. 2018 ; Vol. 7. pp. 1-32.
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abstract = "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 Ca2+ 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 anti-diabetic 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.",
author = "Isabelle Arnoux and Michael Willam and Nadine Griesche and Jennifer Krummeich and Hirofumi Watari and Nina Offermann and Stephanie Weber and {Narayan Dey}, Partha and Changwei Chen and Olivia Monteiro and Sven Buettner and Katharina Meyer and Daniele Bano and Konstantin Radyushkin and Rosamund Langston and Lambert, {Jeremy J.} and Erich Wanker and Axel Methner and Sybille Krauss and Susann Schweiger and Albrecht Stroh",
note = "This study was funded by the European Huntington Disease Network (A.S. and A.M.), the Focus Program Translational Neurosciences (FTN; I.A., M.W., Su.S., A.S., A.M.) and the BMBF (Eurostars) to AS and was supported by Tenovus Scotland.",
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Arnoux, I, Willam, M, Griesche, N, Krummeich, J, Watari, H, Offermann, N, Weber, S, Narayan Dey, P, Chen, C, Monteiro, O, Buettner, S, Meyer, K, Bano, D, Radyushkin, K, Langston, R, Lambert, JJ, Wanker, E, Methner, A, Krauss, S, Schweiger, S & Stroh, A 2018, 'Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease', eLife, vol. 7, e38744, pp. 1-32. https://doi.org/10.7554/eLife.38744

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 (Lead / Corresponding author); Stroh, Albrecht (Lead / Corresponding author).

In: eLife, Vol. 7, e38744, 04.09.2018, p. 1-32.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease

AU - Arnoux, Isabelle

AU - Willam, Michael

AU - Griesche, Nadine

AU - Krummeich, Jennifer

AU - Watari, Hirofumi

AU - Offermann, Nina

AU - Weber, Stephanie

AU - Narayan Dey, Partha

AU - Chen, Changwei

AU - Monteiro, Olivia

AU - Buettner, Sven

AU - Meyer, Katharina

AU - Bano, Daniele

AU - Radyushkin, Konstantin

AU - Langston, Rosamund

AU - Lambert, Jeremy J.

AU - Wanker, Erich

AU - Methner, Axel

AU - Krauss, Sybille

AU - Schweiger, Susann

AU - Stroh, Albrecht

N1 - This study was funded by the European Huntington Disease Network (A.S. and A.M.), the Focus Program Translational Neurosciences (FTN; I.A., M.W., Su.S., A.S., A.M.) and the BMBF (Eurostars) to AS and was supported by Tenovus Scotland.

PY - 2018/9/4

Y1 - 2018/9/4

N2 - 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 Ca2+ 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 anti-diabetic 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.

AB - 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 Ca2+ 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 anti-diabetic 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.

U2 - 10.7554/eLife.38744

DO - 10.7554/eLife.38744

M3 - Article

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VL - 7

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JO - eLife

JF - eLife

SN - 2050-084X

M1 - e38744

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Arnoux I, Willam M, Griesche N, Krummeich J, Watari H, Offermann N et al. Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. eLife. 2018 Sep 4;7:1-32. e38744. https://doi.org/10.7554/eLife.38744