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

Hamid Meziane, Malik Khelfaoui, Noemi Morello, Bassem Hiba, Eleonora Calcagno, Sophie Reibel-Foisset, Mohammed Selloum, Jamel Chelly, Yann Humeau, Fabrice Riet, Ginevra Zanni, Yann Herault, Thierry Bienvenu, Maurizio Giustetto, Pierre Billuart

Research output: Contribution to journalArticle

Abstract

Loss of functionmutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodentmodels suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiologicalmechanisms with other cognitive disorders. Variants of this gene have been also identified in autismspectrumdisorder and schizophrenia. The advanced understanding of themechanisms 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 amousemodel of the OPHN1 loss of function. Here, we report that chronic treatment in adultmouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognitionmemory and limits the brain ventricular dilatation observed in Ophn1-/y. However, deficits in working and spatialmemories 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.

Original languageEnglish
Pages (from-to)2314-2323
Number of pages10
JournalHuman Molecular Genetics
Volume25
Issue number11
DOIs
Publication statusPublished - Jun 1 2016

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Intellectual Disability
rho-Associated Kinases
Brain
Synaptic Transmission
Cerebral Ventricles
Neuronal Plasticity
ras Genes
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Genes
Dilatation
Schizophrenia
fasudil
Mouse Ophn1 protein
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability. / Meziane, Hamid; Khelfaoui, Malik; Morello, Noemi; Hiba, Bassem; Calcagno, Eleonora; Reibel-Foisset, Sophie; Selloum, Mohammed; Chelly, Jamel; Humeau, Yann; Riet, Fabrice; Zanni, Ginevra; Herault, Yann; Bienvenu, Thierry; Giustetto, Maurizio; Billuart, Pierre.

In: Human Molecular Genetics, Vol. 25, No. 11, 01.06.2016, p. 2314-2323.

Research output: Contribution to journalArticle

Meziane, H, Khelfaoui, M, Morello, N, Hiba, B, Calcagno, E, Reibel-Foisset, S, Selloum, M, Chelly, J, Humeau, Y, Riet, F, Zanni, G, Herault, Y, Bienvenu, T, Giustetto, M & Billuart, P 2016, 'Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability', Human Molecular Genetics, vol. 25, no. 11, pp. 2314-2323. https://doi.org/10.1093/hmg/ddw102
Meziane, Hamid ; Khelfaoui, Malik ; Morello, Noemi ; Hiba, Bassem ; Calcagno, Eleonora ; Reibel-Foisset, Sophie ; Selloum, Mohammed ; Chelly, Jamel ; Humeau, Yann ; Riet, Fabrice ; Zanni, Ginevra ; Herault, Yann ; Bienvenu, Thierry ; Giustetto, Maurizio ; Billuart, Pierre. / Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 11. pp. 2314-2323.
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