X-linked or autosomal rare mental retardation syndromes: phenotypic analysis in transgenic mouse models.

Some rare defects caused by mutations in genes encoding transcriptional regulators that orchestrate the brain differentiation and functioning are involved in Mental Retardation (MR). A gene mutation, namely the X-linked Methyl-CpG- binding protein 2 (MeCP2), is responsible for Rett Syndrome, a severe neurodevelopmental disorder, and the second genetic cause of mental retardation affecting 1 on 20,000 girls. Clinical characteristics appear between 6 and 18 months of age. Recently however, subtle deficits have been shown to appear in younger infants. So far, mouse models have been behaviourally and neurochemically characterized mainly at the adult stage. We will focus the early phases of development (spontaneous motor and emotional behaviour) of the Mecp2-308 mutant mice. Such analysis can be especially informative in models of human neurodevelopmental disorders with neurological and cognitive symptoms already during infancy. To evaluate possible neuronal effects of MeCP2 gene alterations, morphological analysis on growth and remodeling of dendrites and spines as well as evaluation of neurotrophin (NGF, BDNF) levels will be carried out. We will perform a preclinical evaluation of two different therapeutic strategies: i) perinatal supplementation with choline on onset and time-course of those behavioral endpoints sensitive to Mecp2 mutation; ii) rearing in socially and physically enriched environment early in development. Both these strategies are reported to stimulate growth actors and synaptic plasticity. Results are expected to identify early markers of the disease and provide useful relevant indications for the development of non-pharmacological interventions within clinical settings. Regarding a rare autosomal form of MR, we will analyze Kruppel-Like Factor 7 (KLF7) alterations (polymorphism and point mutations), a gene mapping on chromosome 2q31-33, a region associated with MR and autism. KFL7 is a strong candidate as a brain developmental gene associated with altered neuronal plasticity and intellectual disorders. A systematic search of KLF7 genomic alteration in a cohort of 110 Sardinian patients of both genders with various degree of mental retardation (with or without autism) will be performed. Such analysis will allow to test KFL7 involvement in hereditary neurodevelopmental disorders associated with cognitive disabilities, and will offer an important an valuable tool to identify new targets for innovative drugs and therapeutic strategies.