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Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity.

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-dependent 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.

Pubmed ID: 17728457


  • Khelfaoui M
  • Denis C
  • van Galen E
  • de Bock F
  • Schmitt A
  • Houbron C
  • Morice E
  • Giros B
  • Ramakers G
  • Fagni L
  • Chelly J
  • Nosten-Bertrand M
  • Billuart P


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

August 29, 2007

Associated Grants


Mesh Terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Cells, Cultured
  • Cerebral Ventricles
  • Cytoskeletal Proteins
  • Dendritic Spines
  • Exploratory Behavior
  • Female
  • GTP Phosphohydrolases
  • GTPase-Activating Proteins
  • Hippocampus
  • Male
  • Maze Learning
  • Memory Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Neurons
  • Nuclear Proteins
  • Peptide Fragments
  • Silver Staining
  • Social Behavior Disorders
  • Spatial Behavior
  • rac1 GTP-Binding Protein