Journal Article

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

Monteiro, Olivia, Chen, Changwei, Krummeich, Jennifer, Watari, Hirofumi, Radyushkin, Konstantin, Offermann, Nina, Narayan Dey, Partha, Lambert, Jeremy J, Willam, Michael, Methner, Axel, Krauss, Sybille, Griesche, Nadine, Schweiger, Susann, Stroh, Albrecht, Weber, Stephanie, Bano, Daniele, Buettner, Sven, Meyer, Katharina, Wanker, Erich, Arnoux, Isabelle, Langston, Rosamund

2018

Overview

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 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. Huntington’s disease is a devastating brain disorder that causes severe mood disorders, problems with moving, and dementia. Most people develop the condition between their thirties and fifties, and die a decade or two after the symptoms first appear. The disease emerges because of a mutation in the gene for the Huntingtin protein, which leads to neurons slowly dying in the brain. While genetic testing can reveal who carries the faulty gene, no treatment addresses the root of the disorder or prevents it from appearing. Instead, most therapies for Huntington’s disease aim to reduce brain damage once the telltale symptoms are already present. However, the disease-causing protein is expressed early during the life of a patient, which could give it time to damage the brain long before neurons die and the disorder reveals itself. Treatments that start after the first signs of the disease may be too late to reverse the damage. Detecting and preventing early brain changes in people that carry the mutation may thus help to stop the disease from progressing. Here, Arnoux, Willam, Griesche et al. set out to detect the minute changes that the faulty Huntingtin protein may cause in the brain network of young mice with the mutation. State-of-the-art imaging tools helped to examine individual neurons in the brain area that processes visual information. These experiments revealed that a group of brain cells had become hyperactive; once this change had occurred, the mutant animals were less anxious than is typical for mice. Metformin is a drug used to treat diabetes, but it also interferes with a structure that is required to produce the disease-causing Huntingtin protein. Arnoux et al. therefore explored whether the compound could rescue the early brain alterations observed in mutant mice. Adding metformin in the water of the animals for three weeks halted the production of the mutant protein, reversed the brain changes and stopped the abnormal behavior. Further work is now required in humans to confirm that Huntington’s disease starts with a change in the activity of networks in the brain, and to verify that metformin can stop the disorder in its track.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: 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