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The Journal of Neuroscience, August 29, 2007, 27(35):9439-9450; doi:10.1523/JNEUROSCI.2029-07.2007

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Development/Plasticity/Repair
Loss of X-Linked Mental Retardation Gene Oligophrenin1 in Mice Impairs Spatial Memory and Leads to Ventricular Enlargement and Dendritic Spine Immaturity

Malik Khelfaoui,^1,2 Cécile Denis,³ Elly van Galen,⁴ Frédéric de Bock,^5,6 Alain Schmitt,^1,2 Christophe Houbron,^1,2 Elise Morice,³ Bruno Giros,³ Ger Ramakers,⁴ Laurent Fagni,^5,6 Jamel Chelly,^1,2 Marika Nosten-Bertrand,³ and Pierre Billuart^1,2

¹Department of Genetic and Development, Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS) [Unité Mixte de Recherche (UMR) 8104], F-75014 Paris, France, ²Inserm, U567, F-75014 Paris, France, ³Inserm, U513, Neurobiology and Psychiatry, F-94010 Créteil, France, ⁴Netherlands Institute for Neurosciences, Neurons, and Networks, 1105 AZ Amsterdam, The Netherlands, ⁵Department of Neurobiology, Institut de Genomique Fonctionnelle, Université Montpellier 1 et 2, CNRS (UMR 5203), F-34094 Montpellier, France, and ⁶Inserm, U661, F-34094 Montpellier, France

Correspondence should be addressed to Dr. Pierre Billuart, Department of Genetic and Development, Institut Cochin, 24 rue du Fabourg St. Jacques, F-75014, Paris, France. Email: billuart{at}cochin.inserm.fr

Loss of oligophrenin1 (OPHN1) function in human causes X-linked mental retardation associated with cerebellar hypoplasia and, in some cases, with lateral ventricle enlargement. In vitro studies showed that ophn1 regulates dendritic spine through the control of Rho GTPases, but its in vivo function remains unknown. We generated a mouse model of ophn1 deficiency and showed that it mimics the ventricles enlargement without affecting the cerebellum morphoanatomy. The ophn1 knock-out mice exhibit behavioral defects in spatial memory together with impairment in social behavior, lateralization, and hyperactivity. Long-term potentiation and mGluR-dependant long-term depression are normal in the CA1 hippocampal area of ophn1 mutant, whereas paired-pulse facilitation is reduced. This altered short-term plasticity that reflects changes in the release of neurotransmitters from the presynaptic processes is associated with normal synaptic density together with a reduction in mature dendritic spines. In culture, inactivation of ophn1 function increases the density and proportion of immature spines. Using a conditional model of loss of ophn1 function, we confirmed this immaturity defect and showed that ophn1 is required at all the stages of the development. These studies show that, depending of the context, ophn1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia. Altogether, these observations indicate that cognitive impairment related to OPHN1 loss of function is associated with both presynaptic and postsynaptic alterations.

Key words: X-linked mental retardation; ophn1 knock-out; dendritic spines; brain ventricular enlargement; hippocampal plasticity; learning and memory

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Received Oct. 27, 2006; revised June 25, 2007; accepted July 17, 2007.

Correspondence should be addressed to Dr. Pierre Billuart, Department of Genetic and Development, Institut Cochin, 24 rue du Fabourg St. Jacques, F-75014, Paris, France. Email: billuart{at}cochin.inserm.fr

This article has been cited by other articles:

				M. Khelfaoui, A. Pavlowsky, A. D. Powell, P. Valnegri, K. W. Cheong, Y. Blandin, M. Passafaro, J. G.R. Jefferys, J. Chelly, and P. Billuart Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation Hum. Mol. Genet., July 15, 2009; 18(14): 2575 - 2583. [Abstract] [Full Text] [PDF]

				N. Nadif Kasri, A. Nakano-Kobayashi, R. Malinow, B. Li, and L. Van Aelst The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors Genes & Dev., June 1, 2009; 23(11): 1289 - 1302. [Abstract] [Full Text] [PDF]

				C. Sawallisch, K. Berhorster, A. Disanza, S. Mantoani, M. Kintscher, L. Stoenica, A. Dityatev, S. Sieber, S. Kindler, F. Morellini, et al. The Insulin Receptor Substrate of 53 kDa (IRSp53) Limits Hippocampal Synaptic Plasticity J. Biol. Chem., April 3, 2009; 284(14): 9225 - 9236. [Abstract] [Full Text] [PDF]

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