Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-09-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/38744 |
| _version_ | 1797997528129470464 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Isabelle Arnoux |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:34:14Z |
| format | Article |
| id | doaj.art-031434054df44d4c9f2caf98fe3f48e2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:34:14Z |
| publishDate | 2018-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-031434054df44d4c9f2caf98fe3f48e22022-12-22T04:29:20ZengeLife Sciences Publications LtdeLife2050-084X2018-09-01710.7554/eLife.38744Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s diseaseIsabelle Arnoux0https://orcid.org/0000-0003-4530-9944Michael Willam1Nadine Griesche2Jennifer Krummeich3Hirofumi Watari4Nina Offermann5Stephanie Weber6Partha Narayan Dey7Changwei Chen8Olivia Monteiro9Sven Buettner10Katharina Meyer11Daniele Bano12Konstantin Radyushkin13Rosamund Langston14Jeremy J Lambert15Erich Wanker16https://orcid.org/0000-0001-8072-1630Axel Methner17https://orcid.org/0000-0002-8774-0057Sybille Krauss18Susann Schweiger19Albrecht Stroh20https://orcid.org/0000-0001-9410-4086Institute of Pathophysiology, Focus Program Translational Neurosciences, University Medical Center, Mainz, GermanyInstitute for Human Genetics, University Medical Center, Mainz, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyInstitute for Human Genetics, University Medical Center, Mainz, GermanyInstitute of Pathophysiology, Focus Program Translational Neurosciences, University Medical Center, Mainz, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyDepartment for Neurology, University Medical Center, Mainz, GermanyDivision of Neurosciences, Ninewells Hospital and Medical School, Dundee, United KingdomDivision of Neurosciences, Ninewells Hospital and Medical School, Dundee, United KingdomGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyMouse Behavior Unit, University Medical Center, Mainz, GermanyDivision of Neurosciences, Ninewells Hospital and Medical School, Dundee, United Kingdom; Mouse Behavior Unit, University Medical Center, Mainz, GermanyDivision of Neurosciences, Ninewells Hospital and Medical School, Dundee, United KingdomDepartment of Neuroproteomics, Max-Delbrück-Center, Berlin, GermanyDepartment for Neurology, University Medical Center, Mainz, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyInstitute for Human Genetics, University Medical Center, Mainz, GermanyInstitute of Pathophysiology, Focus Program Translational Neurosciences, University Medical Center, Mainz, GermanyCatching 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.https://elifesciences.org/articles/38744Huntington diseasein vivo calcium imagingcortical microcircuitsneuronal hyperactivitymetformin |
| spellingShingle | 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 Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease eLife Huntington disease in vivo calcium imaging cortical microcircuits neuronal hyperactivity metformin |
| title | Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease |
| title_full | Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease |
| title_fullStr | Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease |
| title_full_unstemmed | Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease |
| title_short | Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease |
| title_sort | metformin reverses early cortical network dysfunction and behavior changes in huntington s disease |
| topic | Huntington disease in vivo calcium imaging cortical microcircuits neuronal hyperactivity metformin |
| url | https://elifesciences.org/articles/38744 |
| work_keys_str_mv | AT isabellearnoux metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT michaelwillam metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT nadinegriesche metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT jenniferkrummeich metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT hirofumiwatari metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT ninaoffermann metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT stephanieweber metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT parthanarayandey metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT changweichen metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT oliviamonteiro metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT svenbuettner metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT katharinameyer metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT danielebano metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT konstantinradyushkin metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT rosamundlangston metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT jeremyjlambert metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT erichwanker metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT axelmethner metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT sybillekrauss metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT susannschweiger metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease AT albrechtstroh metforminreversesearlycorticalnetworkdysfunctionandbehaviorchangesinhuntingtonsdisease |