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 anti-diabetic 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.
| Original language | English |
|---|---|
| Article number | e38744 |
| Pages (from-to) | 1-32 |
| Number of pages | 32 |
| Journal | eLife |
| Volume | 7 |
| DOIs | |
| Publication status | Published - 4 Sep 2018 |
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Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. / 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 (Lead / Corresponding author); Stroh, Albrecht (Lead / Corresponding author).
In: eLife, Vol. 7, e38744, 04.09.2018, p. 1-32.Research output: Contribution to journal › Article
TY - JOUR
T1 - Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease
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 - Buettner, 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
N1 - This study was funded by the European Huntington Disease Network (A.S. and A.M.), the Focus Program Translational Neurosciences (FTN; I.A., M.W., Su.S., A.S., A.M.) and the BMBF (Eurostars) to AS and was supported by Tenovus Scotland.
PY - 2018/9/4
Y1 - 2018/9/4
N2 - 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 anti-diabetic 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.
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 anti-diabetic 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.
U2 - 10.7554/eLife.38744
DO - 10.7554/eLife.38744
M3 - Article
C2 - 30179155
VL - 7
SP - 1
EP - 32
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e38744
ER -