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Human Molecular Genetics Advance Access published online on April 28, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp189
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation

Malik Khelfaoui1,2, Pavlowsky Alice1,2, Andrew D. Powell3, Pamela Valnegri4, Kenneth W. Cheong3, Yann Blandin1,2, Maria Passafaro4, John G.R. Jefferys3, Jamel Chelly1,2 and Pierre Billuart1,2,*

1 Institut Cochin; Université Paris Descartes; CNRS UMR8104; 24 rue du Faubourg Saint Jacques, 75014 Paris, France 2 INSERM U567, 22 rue Méchain, 75014 Paris, France 3 School of Clinical and Experimental Medicine (Neuroscience), The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK 4 DTT- CNR Institute of Neuroscience, 32 via Vanvitelli, 20129, Milano, Italy

* To whom correspondence should be addressed: Pierre Billuart, 24 rue du Faubourg Saint Jacques, 75014 Paris, France; Tel: 33 1 44 41 24 81; Fax: 33 1 44 41 24 21; Email: pierre.billuart{at}inserm.fr

Received March 2, 2009; Revised April 21, 2009; Accepted April 21, 2009

The patho-physiological hypothesis of mental retardation caused by the deficiency of the RhoGAP Oligophrenin1 (OPHN1), relies on the well-known functions of Rho GTPases on neuronal morphology, ie dendritic spine structure. Here we describe a new function of this Bin/Amphiphysin/Rvs (BAR) domain containing protein in the control of clathrin-mediated endocytosis (CME). Through interactions with Src Homology 3 (SH3) domain containing proteins involved in CME, OPHN1 is concentrated to endocytic sites where it down-regulates the RhoA/ROCK signaling pathway and represses the inhibitory function of ROCK on endocytosis. Indeed disruption of Ophn1 in mice reduces the endocytosis of synaptic vesicles and the post-synaptic AMPA receptor internalization, resulting in almost a complete loss of long-term depression (LTD) in the hippocampus. Finally, pharmacological inhibition of this pathway by ROCK inhibitors fully rescued not only the CME deficit in OPHN1 null cells but also synaptic plasticity in the hippocampus from Ophn1 null model. Altogether, we uncovered a new pathophysiological mechanism for intellectual disabilities associated to mutations in RhoGTPases linked genes and also opened new directions for therapeutic approaches of congenital mental retardation.


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