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

Abstract

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 mGluRdependant 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.

Cerebellar development and disease

“…For example, mutations in Oligophrenin 1 (OPHN1), a widely expressed gene encoding a rhoGAP protein, cause X-linked mental retardation and CVH, but never DWM [62][63][64]. In vitro and in vivo experiments have demonstrated a role for Ophn1 in dendritic spine morphogensis in hippocampal neurons in mice, although no gross cerebellar anatomical abnormalities were observed in Ophn1 mutant mice [65,66]. Thus, the basis of human OPHN1-dependent CVH remains obscure.…”

A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα

“…One of the genes responsible for XLID is OPHN1, which encodes a synaptic RhoGTPaseactivating protein (oligophrenin-1) that, among other things, regulates dendritic spine shape in the brain [5][6][7] . OPHN1 involvement in XLID was established by the identification of XLID-associated OPHN1 mutations (balanced translocation t (X; 12) or frameshift deletion) in XLID patients 8 .…”

“…The oligophrenin-1 protein comprises an amino terminal BAR (Bin-Amphiphysin-Rvs) domain which binds curved membranes; a pleckstrin homology domain thought to confer membrane binding specificity through interaction with phosphoinositides; a central RhoGAP domain; and three carboxyl-terminal proline-rich sequences, which are putative SH3-binding sites for endocytic adaptor proteins 7,8,12 . Oligophrenin-1 is broadly expressed in brain with enrichment in the hippocampus, cortex, and cerebellum.…”

“…Oligophrenin-1 is also associated with Homer 6 , an adaptor molecule that influences dendritic spine morphology and synaptic transmission through interaction with Shank and with glutamate receptors [13][14][15] . In hippocampal slices and neuronal cultures, inactivation of oligophrenin-1 function affects the maturation and reduces the density of dendritic spines 6,7,12 . The oligophrenin-1 (ophn1) knockout mouse has impaired spatial learning, altered social behavior, novelty-driven hyperactivity, and enlarged cerebral ventricles 7 .…”

“…In hippocampal slices and neuronal cultures, inactivation of oligophrenin-1 function affects the maturation and reduces the density of dendritic spines 6,7,12 . The oligophrenin-1 (ophn1) knockout mouse has impaired spatial learning, altered social behavior, novelty-driven hyperactivity, and enlarged cerebral ventricles 7 . Loss of oligophrenin-1 also reduces synaptic vesicle endocytosis in 4 the pre-synaptic compartment 12,16 and affects the internalization and stability of AMPA receptors post-synaptically 12,16 .…”