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100 1 _ |a Arnoux, Isabelle
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245 _ _ |a Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease.
260 _ _ |a Cambridge
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264 _ 1 |3 online
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520 _ _ |a 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.
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650 _ 7 |a Huntingtin Protein
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650 _ 7 |a Mutant Proteins
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650 _ 7 |a Protein Aggregates
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650 _ 7 |a Metformin
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650 _ 7 |a Calcium
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650 _ 2 |a Animals
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650 _ 2 |a Astrocytes: drug effects
|2 MeSH
650 _ 2 |a Astrocytes: metabolism
|2 MeSH
650 _ 2 |a Behavior, Animal: drug effects
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: drug effects
|2 MeSH
650 _ 2 |a Calcium: metabolism
|2 MeSH
650 _ 2 |a Cell Respiration: drug effects
|2 MeSH
650 _ 2 |a Cerebral Cortex: drug effects
|2 MeSH
650 _ 2 |a Cerebral Cortex: physiopathology
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Huntingtin Protein: metabolism
|2 MeSH
650 _ 2 |a Huntington Disease: pathology
|2 MeSH
650 _ 2 |a Huntington Disease: physiopathology
|2 MeSH
650 _ 2 |a Kinetics
|2 MeSH
650 _ 2 |a Metformin: pharmacology
|2 MeSH
650 _ 2 |a Mitochondria: drug effects
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Mutant Proteins: metabolism
|2 MeSH
650 _ 2 |a Nerve Net: drug effects
|2 MeSH
650 _ 2 |a Nerve Net: physiopathology
|2 MeSH
650 _ 2 |a Neurons: drug effects
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Photons
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650 _ 2 |a Protein Aggregates: drug effects
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650 _ 2 |a Protein Biosynthesis
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650 _ 2 |a Time-Lapse Imaging
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Marc 21