Altered brain morphology in a mouse model of mental retardation Mental retardation (MR) affects 2-3% of the population; those due to X-linked mutations are a common cause of moderate to severe MR. OPHN1 (Ophn-1 in mice) is one of the genes implicated in X-linked mental retardation (XLMR), encoding oligophrenin-1, a RhoGAP protein. Loss of function mutations affect Rho GTPase-dependent signalling pathways and alter actin cytoskeleton dynamics which are important for many neuronal functions, including morphogenesis and neuroepithelial development. Structural abnormalities, namely, abnormal cerebral ventricles typically associated with hydrocephalus, have been shown in brains of MR patients with OPHN1 mutations and Ophn-1 null mice. A systematic study has been conducted to explore alterations in brain anatomy in Ophn-1 mice. Ophn-1 mice (male 15-30g, 6 week old (n=6 for both genotypes) and 3 month old (Ophn-1+/y n=8 and Ophn-1-/y n=6)) were anaesthetised by I.P. injection of medetomidine (1mg/kg) and ketamine (76mg/kg). Values are expressed as mean ± S.E.M, analysed by ANOVA or Student’s t-test. To investigate the impact of loss of oligophrenin-1 on cerebral ventricles, ventricular volumes were analysed. Lateral ventricles were larger in Ophn-1-/y mice than Ophn-1+/y mice at 6 weeks of age (26.2±10.5 mm3 and 3.81±0.44 mm3; respectively; p=0.002) and 3 months of age (7.78±2.54 mm3 and 3.42±6.99 mm3; respectively; p=0.02). Lateral ventricle dilatation was associated with a reduction in motor cortex thickness (6 weeks: Ophn-1-/y 0.91±0.05 mm and Ophn-1+/y 1.09±0.03 mm; p=0.016 and 3 months: Ophn-1-/y 0.94±0.03 mm and Ophn-1+/y 1.04±0.02 mm; p=0.04) without alteration in somatosensory, auditory and ectorhinal cortices. Hippocampal volume was similar in Ophn-1+/y and Ophn-1-/y mice (7.38±1.40 mm3 and 9.29±0.7 mm3; respectively; p=0.23), neither the thalamus area (15.78±0.91 mm2 and 13.46±0.69 mm2; respectively; p=0.07) nor total brain area (51.8±1.6 mm2 and 46.9±3.05 mm2 respectively; p=0.18) were affected. This study demonstrates brain malformation in Ophn-1-/y mice, primarily expansion of the lateral ventricles, which may be due to loss of oligophrenin-1 expression in ependymal cells, chorial villi or endothelium. Thus, this could result in impairments in cilia function, ependymal proliferation, abnormal production/absorption of cerebral spinal fluid or obstruction of cerebral aqueduct and/or fourth ventricle. How the ventriculomegaly and reduction in cortical thickness contribute to the cognitive deficits remains to be explored.