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

Elife. 2018 Sep 4;7:e38744. doi: 10.7554/eLife.38744.

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: C. elegans; Huntington disease; cortical microcircuits; in vivo calcium imaging; metformin; mouse; neuronal hyperactivity; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

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

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.