Arnoux, Isabelle1; Willam, Michael1; Griesche, Nadine2; Krummeich, Jennifer1; Watari, Hirofumi1; Offermann, Nina2; Weber, Stephanie2; Narayan Dey, Partha1; Chen, Chen3; Monteiro, Olivia4; Buettner, Sven2; Meyer, Katharina2; Bano, Daniele2; Radyushkin, Konstantin1; Langston, Rosamund1; Lambert, Jeremy J.2; Wanker, Erich5; Methner, Axel1; Krauss, Sybille2; Schweiger, Susann1; Stroh, Albrecht1

Published Sep 05, 2018 on Dryad. https://doi.org/10.5061/dryad.g3b5272

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.

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Data from: Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

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