title: Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability.
abstract: 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-/yHowever, 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.
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; GIE CERBM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, UMR7104, INSERM, U964, University of Strasbourg, F-67404 Illkirch-Graffenstaden, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, 75014, France Institut interdisciplinaire de neuroscience, CNRS UMR5297, University of Bordeaux, Bordeaux, 33077, France.
authors.forename: Malik
authors.initials: M
authors.lastname: Khelfaoui
authors.affiliation: University of Torino, Department of Neuroscience « Rita Levi Montalcini », National Institute of Neuroscience-Italy, Torino, 10126, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Morello
authors.affiliation: Centre de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS, Université de Bordeaux, 33077, Bordeaux, France.
authors.forename: Bassem
authors.initials: B
authors.lastname: Hiba
authors.affiliation: University of Torino, Department of Neuroscience « Rita Levi Montalcini », National Institute of Neuroscience-Italy, Torino, 10126, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Calcagno
authors.affiliation: Chronobioton, CNRS, Universite Strasbourg, UMS3415, Strasbourg, 67084 France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Reibel-Foisset
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; GIE CERBM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, UMR7104, INSERM, U964, University of Strasbourg, F-67404 Illkirch-Graffenstaden, France.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Selloum
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; GIE CERBM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, UMR7104, INSERM, U964, University of Strasbourg, F-67404 Illkirch-Graffenstaden, France Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, 75014, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Institut interdisciplinaire de neuroscience, CNRS UMR5297, University of Bordeaux, Bordeaux, 33077, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; GIE CERBM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, UMR7104, INSERM, U964, University of Strasbourg, F-67404 Illkirch-Graffenstaden, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Riet
authors.affiliation: Department of Neurosciences, Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, 00165, Rome, Italy.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; GIE CERBM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, UMR7104, INSERM, U964, University of Strasbourg, F-67404 Illkirch-Graffenstaden, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, 75014, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.affiliation: University of Torino, Department of Neuroscience « Rita Levi Montalcini », National Institute of Neuroscience-Italy, Torino, 10126, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Giustetto
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, 75014, France pierre.billuart@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000328:Adult; D000818:Animals; D000067877:Autism Spectrum Disorder; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D009435:Synaptic Transmission
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil