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

• Published in: eLife Vol. 7
• Main Authors: Arnoux, Isabelle, Willam, Michael, Griesche, Nadine, Krummeich, Jennifer, Watari, Hirofumi, Offermann, Nina, Weber, Stephanie, Narayan Dey, Partha, Chen, Changwei, 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
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 04-09-2018; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Activity patterns; Animal behavior; Animals; Antidiabetics; Astrocytes - drug effects; Astrocytes - metabolism; Behavior; Behavior modification; Behavior, Animal - drug effects; Brain; Brain damage; Caenorhabditis elegans - drug effects; Calcium - metabolism; Calcium imaging; Cell Respiration - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - physiopathology; cortical microcircuits; Dementia; Development and progression; Diabetes mellitus; Diabetes therapy; Disease; Disease Models, Animal; Genes; Genetic testing; Huntingtin; Huntingtin Protein - metabolism; Huntington disease; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntingtons disease; Hyperactivity; Hypoglycemic agents; in vivo calcium imaging; Kinetics; Membranes; Metformin; Metformin - pharmacology; Mitochondria - drug effects; Mitochondria - metabolism; Mutant Proteins - metabolism; Nerve Net - drug effects; Nerve Net - physiopathology; Neurodegeneration; Neuroimaging; neuronal hyperactivity; Neurons; Neurons - drug effects; Neurons - metabolism; Neuroscience; Neurosciences; Photons; Protein Aggregates - drug effects; Protein Biosynthesis; Proteins; Time-Lapse Imaging; Visual cortex; Mainz Germany; United States > US; Germany; mouse; C. elegans; cortical microcircuits; neuroscience; Huntington disease; in vivo calcium imaging; metformin; neuronal hyperactivity
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.38744

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
two-photon Ca
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 antidiabetic 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.