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@ARTICLE{Arnoux:140227,
author = {Arnoux, Isabelle and Willam, Michael and Griesche, Nadine
and Krummeich, Jennifer and Watari, Hirofumi and Offermann,
Nina and Weber, Stephanie and Narayan Dey, Partha and Chen,
Changwei and Monteiro, Olivia and Büttner, Sven and Meyer,
Katharina and Bano, Daniele and Radyushkin, Konstantin and
Langston, Rosamund and Lambert, Jeremy J and Wanker, Erich
and Methner, Axel and Krauß, Sybille and Schweiger, Susann
and Stroh, Albrecht},
title = {{M}etformin reverses early cortical network dysfunction and
behavior changes in {H}untington's disease.},
journal = {eLife},
volume = {7},
issn = {2050-084X},
address = {Cambridge},
publisher = {eLife Sciences Publications},
reportid = {DZNE-2020-06549},
pages = {e38744},
year = {2018},
abstract = {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.},
keywords = {Animals / Astrocytes: drug effects / Astrocytes: metabolism
/ Behavior, Animal: drug effects / Caenorhabditis elegans:
drug effects / Calcium: metabolism / Cell Respiration: drug
effects / Cerebral Cortex: drug effects / Cerebral Cortex:
physiopathology / Disease Models, Animal / Huntingtin
Protein: metabolism / Huntington Disease: pathology /
Huntington Disease: physiopathology / Kinetics / Metformin:
pharmacology / Mitochondria: drug effects / Mitochondria:
metabolism / Mutant Proteins: metabolism / Nerve Net: drug
effects / Nerve Net: physiopathology / Neurons: drug effects
/ Neurons: metabolism / Photons / Protein Aggregates: drug
effects / Protein Biosynthesis / Time-Lapse Imaging /
Huntingtin Protein (NLM Chemicals) / Mutant Proteins (NLM
Chemicals) / Protein Aggregates (NLM Chemicals) / Metformin
(NLM Chemicals) / Calcium (NLM Chemicals)},
cin = {AG Krauß / AG Bano / AG Nicotera},
ddc = {600},
cid = {I:(DE-2719)1011006 / I:(DE-2719)1013003 /
I:(DE-2719)5000018},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342) / 341
- Molecular Signaling (POF3-341)},
pid = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-341},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30179155},
pmc = {pmc:PMC6156080},
doi = {10.7554/eLife.38744},
url = {https://pub.dzne.de/record/140227},
}