Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease
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.
Reviewing Editor
- Harry T Orr, University of Minnesota, United States
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).
Version 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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