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

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.

• Authors: Isabelle Arnoux, Michael Willam, Nadine Griesche, Jennifer Krummeich, Hirofumi Watari, Nina Offermann, Stephanie Weber, Partha Narayan Dey, Changwei Chen, Olivia Monteiro, Sven Buettner, Katharina Meyer, Daniele Bano, Konstantin Radyushkin, Rosamund Langston, Jeremy J Lambert, Erich Wanker, Axel Methner, Sybille Krauss, Susann Schweiger, Albrecht Stroh
• Journal: eLife (Elife) Vol. 7 (09 04 2018) ISSN: 2050-084X [Electronic] England
• PMID: 30179155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018, Arnoux et al.

Chemical References

• Huntingtin Protein
• Mutant Proteins
• Protein Aggregates
• Metformin
• Calcium

Topics

• Animals
• Astrocytes (drug effects, metabolism)
• Behavior, Animal (drug effects)
• Caenorhabditis elegans (drug effects)
• Calcium (metabolism)
• Cell Respiration (drug effects)
• Cerebral Cortex (drug effects, physiopathology)
• Disease Models, Animal
• Huntingtin Protein (metabolism)
• Huntington Disease (pathology, physiopathology)
• Kinetics
• Metformin (pharmacology)
• Mitochondria (drug effects, metabolism)
• Mutant Proteins (metabolism)
• Nerve Net (drug effects, physiopathology)
• Neurons (drug effects, metabolism)
• Photons
• Protein Aggregates (drug effects)
• Protein Biosynthesis
• Time-Lapse Imaging