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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\u2019s 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\u2019s disease pathogenesis long before the onset of clinical symptoms.<\/jats:p>","DOI":"10.7554\/elife.38744","type":"journal-article","created":{"date-parts":[[2018,9,4]],"date-time":"2018-09-04T08:00:59Z","timestamp":1536048059000},"source":"Crossref","is-referenced-by-count":93,"title":["Metformin reverses early cortical network dysfunction and behavior changes in Huntington\u2019s disease"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4530-9944","authenticated-orcid":true,"given":"Isabelle","family":"Arnoux","sequence":"first","affiliation":[{"name":"Institute of Pathophysiology, Focus Program Translational Neurosciences, University Medical Center, Mainz, 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