Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease
- Johannes Gutenberg University Mainz, Germany
- University Medical Center, Germany
- German Center for Neurodegenerative Diseases (DZNE), Germany
- Ninewells Hospital and Medical School, United Kingdom
- 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.
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Data from: Metformin reverses early cortical network dysfunction and behavior changes in Huntington's diseaseAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
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
- Harry T Orr, University of Minnesota, United States
Publication history
- Received: May 29, 2018
- Accepted: September 2, 2018
- Accepted Manuscript published: September 4, 2018 (version 1)
- Version of Record published: September 25, 2018 (version 2)
- 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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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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