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

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Item Type:Article
Title:Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease
Creators Name:Arnoux, I. and Willam, M. and Griesche, N. and Krummeich, J. and Watari, H. and Offermann, N. and Weber, S. and Narayan Dey, P. and Chen, C. and Monteiro, O. and Buettner, S. and Meyer, K. and Bano, D. and Radyushkin, K. and Langston, R. and Lambert, J.J. and Wanker, E. and Methner, A. and Krauss, S. and Schweiger, S. and Stroh, A.
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 Ca(2+) 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.
Keywords:Huntington Disease, In Vivo Calcium Imaging, Cortical Microcircuits, Neuronal Hyperactivity, Metformin, Animals, Caenorhabditis elegans
Source:eLife
ISSN:2050-084X
Publisher:eLife Sciences Publications (U.K.)
Volume:7
Page Range:e38744
Date:4 September 2018
Official Publication:https://doi.org/10.7554/eLife.38744
PubMed:View item in PubMed

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