38 Arnoux, Isabelle Willam, Michael Griesche, Nadine Krummeich, Jennifer Watari, Hirofumi Offermann, Nina Weber, Stephanie Narayan Dey, Partha Chen, Chen Monteiro, Olivia Buettner, Sven Meyer, Katharina Bano, Daniele Radyushkin, Konstantin Langston, Rosamund Lambert, Jeremy J. Wanker, Erich Methner, Axel Krauss, Sybille Schweiger, Susann Stroh, Albrecht AG Krauß AG Bano AG Capasso Biorepository Dryad 10.5061/dryad.g3b5272 English 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. PUB:(DE-HGF)32, ; 26, ; cortical microcircuits Huntington disease in vivo calcium imaging metformin neuronal hyperactivity Dataset 2018 DZNE-2022-01789 2018 https://pub.dzne.de/record/169082 https://doi.org/10.5061/DRYAD.G3B5272