Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability

Hamid Meziane 1 Malik Khelfaoui 2 Noemi Morello Bassem Hiba 3 Eleonora Calcagno Sophie Reibel-Foisset Mohammed Selloum 4 Jamel Chelly 5 Yann Humeau 6 Fabrice Riet 5 Ginevra Zanni 7 Yann Hérault 8 Thierry Bienvenu 9 Maurizio Giustetto 10 Pierre Billuart 2
1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 UMR_S567 / UMR 8104 - Institut Cochin
3 CREATIS - Centre de Recherche et d'Application en Traitement de l'Image et du Signal
4 ICS - Institut Clinique de la Souris
5 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
6 Interdisciplinary Institute for Neuroscience
7 Medical Genetics and Pediatric Cardiology
8 IEM - Immunologie et embryologie moléculaires
9 Service de biochimie et de génétique moléculaire [CHU Cochin]
10 Dipartimento di Neuroscienza
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 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. †
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Hamid Meziane, Malik Khelfaoui, Noemi Morello, Bassem Hiba, Eleonora Calcagno, et al.. Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability. Human Molecular Genetics, Oxford University Press (OUP), 2016, 25 (11), pp.2314-2323. ⟨10.1093/hmg/ddw102⟩. ⟨hal-02404671⟩

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