TY  - JOUR
AU  - Arnoux, Isabelle
AU  - Willam, Michael
AU  - Griesche, Nadine
AU  - Krummeich, Jennifer
AU  - Watari, Hirofumi
AU  - Offermann, Nina
AU  - Weber, Stephanie
AU  - Narayan Dey, Partha
AU  - Chen, Changwei
AU  - Monteiro, Olivia
AU  - Büttner, Sven
AU  - Meyer, Katharina
AU  - Bano, Daniele
AU  - Radyushkin, Konstantin
AU  - Langston, Rosamund
AU  - Lambert, Jeremy J
AU  - Wanker, Erich
AU  - Methner, Axel
AU  - Krauß, Sybille
AU  - Schweiger, Susann
AU  - Stroh, Albrecht
TI  - Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease.
JO  - eLife
VL  - 7
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DZNE-2020-06549
SP  - e38744
PY  - 2018
AB  - 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.
KW  - Animals
KW  - Astrocytes: drug effects
KW  - Astrocytes: metabolism
KW  - Behavior, Animal: drug effects
KW  - Caenorhabditis elegans: drug effects
KW  - Calcium: metabolism
KW  - Cell Respiration: drug effects
KW  - Cerebral Cortex: drug effects
KW  - Cerebral Cortex: physiopathology
KW  - Disease Models, Animal
KW  - Huntingtin Protein: metabolism
KW  - Huntington Disease: pathology
KW  - Huntington Disease: physiopathology
KW  - Kinetics
KW  - Metformin: pharmacology
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Mutant Proteins: metabolism
KW  - Nerve Net: drug effects
KW  - Nerve Net: physiopathology
KW  - Neurons: drug effects
KW  - Neurons: metabolism
KW  - Photons
KW  - Protein Aggregates: drug effects
KW  - Protein Biosynthesis
KW  - Time-Lapse Imaging
KW  - Huntingtin Protein (NLM Chemicals)
KW  - Mutant Proteins (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - Metformin (NLM Chemicals)
KW  - Calcium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30179155
C2  - pmc:PMC6156080
DO  - DOI:10.7554/eLife.38744
UR  - https://pub.dzne.de/record/140227
ER  -