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.
-
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.
Metrics
-
- 4,243
- Page views
-
- 641
- Downloads
-
- 43
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
How does the representation of naturalistic life events change with age? Here we analyzed fMRI data from 414 children and adolescents (5 - 19 years) as they watched a narrative movie. In addition to changes in the degree of inter-subject correlation (ISC) with age in sensory and medial parietal regions, we used a novel measure (between-group ISC) to reveal age-related shifts in the responses across the majority of the neocortex. Over the course of development, brain responses became more discretized into stable and coherent events and shifted earlier in time to anticipate upcoming perceived event transitions, measured behaviorally in an age-matched sample. However, hippocampal responses to event boundaries actually decreased with age, suggesting a shifting division of labor between episodic encoding processes and schematic event representations between the ages of 5 and 19.
-
- Neuroscience
Chemical neurotransmission constitutes one of the fundamental modalities of communication between neurons. Monitoring release of these chemicals has traditionally been difficult to carry out at spatial and temporal scales relevant to neuron function. To understand chemical neurotransmission more fully, we need to improve the spatial and temporal resolutions of measurements for neurotransmitter release. To address this, we engineered a chemi-sensitive, two-dimensional composite nanofilm that facilitates visualization of the release and diffusion of the neurochemical dopamine with synaptic resolution, quantal sensitivity, and simultaneously from hundreds of release sites. Using this technology, we were able to monitor the spatiotemporal dynamics of dopamine release in dendritic processes, a poorly understood phenomenon. We found that dopamine release is broadcast from a subset of dendritic processes as hotspots that have a mean spatial spread of 3.2 µm (full width at half maximum) and are observed with a mean spatial frequency of 1 hotspot per 7.5 µm of dendritic length. Major dendrites of dopamine neurons and fine dendritic processes, as well as dendritic arbors and dendrites with no apparent varicose morphology participated in dopamine release. Remarkably, these release hotspots colocalized with Bassoon, suggesting that Bassoon may contribute to organizing active zones in dendrites, similar to its role in axon terminals.