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

  1. Isabelle Arnoux
  2. Michael Willam
  3. Nadine Griesche
  4. Jennifer Krummeich
  5. Hirofumi Watari
  6. Nina Offermann
  7. Stephanie Weber
  8. Partha Narayan Dey
  9. Changwei Chen
  10. Olivia Monteiro
  11. Sven Buettner
  12. Katharina Meyer
  13. Daniele Bano
  14. Konstantin Radyushkin
  15. Rosamund Langston
  16. Jeremy J Lambert
  17. Erich Wanker
  18. Axel Methner
  19. Sybille Krauss  Is a corresponding author
  20. Susann Schweiger  Is a corresponding author
  21. Albrecht Stroh  Is a corresponding author
  1. Johannes Gutenberg University Mainz, Germany
  2. University Medical Center, Germany
  3. German Center for Neurodegenerative Diseases (DZNE), Germany
  4. Ninewells Hospital and Medical School, United Kingdom
  5. Max Delbrueck Center, Germany

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.

Data availability

Values used in figures are available on Dryad Digital repository (doi:10.5061/dryad.g3b5272).The code used for the analysis of calcium imaging is attached as a source file.The numerical values for each figure are enclosed as source data files.

The following data sets were generated

Article and author information

Author details

  1. Isabelle Arnoux

    Institute for Pathophysiology, Johannes Gutenberg University Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4530-9944
  2. Michael Willam

    Institute for Human Genetics, University Medical Center, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Nadine Griesche

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Jennifer Krummeich

    Institute of Human Genetics, University Medical Center, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Hirofumi Watari

    Institute for Pathophysiology, Johannes Gutenberg University Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Nina Offermann

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephanie Weber

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Partha Narayan Dey

    Department for Neurology, University Medical Center, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Changwei Chen

    Division of Neurosciences, Ninewells Hospital and Medical School, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Olivia Monteiro

    Division of Neurosciences, Ninewells Hospital and Medical School, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Sven Buettner

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Katharina Meyer

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Daniele Bano

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Konstantin Radyushkin

    Mouse Behavior Unit, University Medical Center, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Rosamund Langston

    Division of Neurosciences, Ninewells Hospital and Medical School, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Jeremy J Lambert

    Division of Neurosciences, Ninewells Hospital and Medical School, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Erich Wanker

    Department of Neuroproteomics, Max Delbrueck Center, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8072-1630
  18. Axel Methner

    Department of Neurology, University Medical Center, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8774-0057
  19. Sybille Krauss

    German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    For correspondence
    Sybille.krauss@dzne.de
    Competing interests
    The authors declare that no competing interests exist.
  20. Susann Schweiger

    Institute of Human Genetics, University Medical Center, Mainz, Germany
    For correspondence
    schweigs@uni-mainz.de
    Competing interests
    The authors declare that no competing interests exist.
  21. Albrecht Stroh

    Institute for Pathophysiology, Johannes Gutenberg University Mainz, Mainz, Germany
    For correspondence
    albrecht.stroh@unimedizin-mainz.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9410-4086

Funding

European Huntington disease network

  • Axel Methner
  • Albrecht Stroh

Focus Program Translational Neuroscience

  • Isabelle Arnoux
  • Michael Willam
  • Axel Methner
  • Susann Schweiger
  • Albrecht Stroh

BMBF Eurostar

  • Isabelle Arnoux
  • Albrecht Stroh

Tenovus Scotland

  • Jeremy J Lambert

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures were performed in accordance with institutional animal welfare guidelines and were approved by the state government of Rhineland-Palatinate, Germany (G14-1-010 and G14-1-017).

Reviewing Editor

  1. Harry T Orr, University of Minnesota, United States

Publication history

  1. Received: May 29, 2018
  2. Accepted: September 2, 2018
  3. Accepted Manuscript published: September 4, 2018 (version 1)
  4. Version of Record published: September 25, 2018 (version 2)
  5. Version of Record updated: October 8, 2018 (version 3)

Copyright

© 2018, Arnoux et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Isabelle Arnoux
  2. Michael Willam
  3. Nadine Griesche
  4. Jennifer Krummeich
  5. Hirofumi Watari
  6. Nina Offermann
  7. Stephanie Weber
  8. Partha Narayan Dey
  9. Changwei Chen
  10. Olivia Monteiro
  11. Sven Buettner
  12. Katharina Meyer
  13. Daniele Bano
  14. Konstantin Radyushkin
  15. Rosamund Langston
  16. Jeremy J Lambert
  17. Erich Wanker
  18. Axel Methner
  19. Sybille Krauss
  20. Susann Schweiger
  21. Albrecht Stroh
(2018)
Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease
eLife 7:e38744.
https://doi.org/10.7554/eLife.38744
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