Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability
| Autor: | Fabrice Riet, Sophie Reibel-Foisset, Noemi Morello, Maurizio Giustetto, Jamel Chelly, Mohammed Selloum, Thierry Bienvenu, Bassem Hiba, Ginevra Zanni, Eleonora Calcagno, Malik Khelfaoui, Yann Humeau, Hamid Meziane, Yann Herault, Pierre Billuart |
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| Přispěvatelé: | Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Interdisciplinary Institute for Neuroscience, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie et de génétique moléculaire [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dipartimento di Neuroscienza, Università degli studi di Torino (UNITO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et embryologie moléculaires (IEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP] |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult RHOA Dendritic spine Autism Spectrum Disorder [SDV]Life Sciences [q-bio] autism Synaptic Transmission 03 medical and health sciences Mice synaptopathies 0302 clinical medicine 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Intellectual disability Neuroplasticity Genetics medicine Animals Humans Molecular Biology Rho-associated protein kinase Genetics (clinical) Loss function biology Behavior Animal GTPase-Activating Proteins Fasudil Brain Nuclear Proteins autism synaptopathies dendritic spines intellectual disability General Medicine dendritic spines medicine.disease 3. Good health Cytoskeletal Proteins Disease Models Animal 030104 developmental biology Schizophrenia intellectual disability biology.protein Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2016, 25 (11), pp.2314-2323. ⟨10.1093/hmg/ddw102⟩ |
| ISSN: | 0964-6906 1460-2083 |
| Popis: | International audience; Loss of function mutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodent models suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiological mechanisms with other cognitive disorders. Variants of this gene have been also identified in autism spectrum disorder and schizophrenia. The advanced understanding of the mechanisms underlying OPHN1-related ID, allowed us to develop a therapeutic approach targeting the Ras homolog gene family, member A (RHOA) signalling pathway and repurpose Fasudil-a well-tolerated Rho Kinase (ROCK) and Protein Kinase A (PKA) inhibitor-as a treatment of ID. We have previously shown ex-vivo its beneficial effect on synaptic transmission and plasticity in a mouse model of the OPHN1 loss of function. Here, we report that chronic treatment in adult mouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognition memory and limits the brain ventricular dilatation observed in Ophn1 À/y. However, deficits in working and spatial memories are partially or not rescued by the treatment. These results highlight the potential of Fasudil treatment in synaptopathies and also the need for multiple therapeutic approaches especially in adult where brain plasticity is reduced. † |
| Databáze: | OpenAIRE |
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