Transgenic Model for Learning Defects: Role of NF1 in Drosophila Visuospatial Learning

摘要

Learning difficulties and attention deficits are observed in 40-50% of children with Neurofibromatosis Type 1 (NF1). Additionally many NFI patients exhibit specific deficits in visuo-spatial tasks such as the Judgment of Line Orientation task. Spatial learning is also disrupted in heterozygous mouse Nf1 mutants and can be rescued by reducing Ras activity either genetically or pharmacologically. Conversely olfactory learning defects observed in Nf1 mutant fruit flies are cAMP-dependent rather than Ras-dependent. Visuo-spatial learning in flies depends on the Central Complex region of the brain which is distinct from the Mushroom Body region that is essential for olfactory learning. We hypothesize that visual learning defects in Nf1 mutant flies will be Ras dependent and that this fruit fly model can be exploited to assay potential therapeutic treatments for NF1 cognitive deficits. We propose to assay visual learning in Nf1 mutant flies and in flies where Ras activity is disrupted in specific regions of the adult brain. This report describes the generation of transgenic fly lines to localize RNAi knockout of NF1 Ras and MAPK and to express RasGAP defective NF1 isoforms using the Gal4/Gal80ts/UAS (TARGET) system for precise temporal and spatial control. We have also assayed olfactory learning acuity in Nf1 mutant flies that have been fed drugs that reduce Ras activity or affect downstream targets of Ras/NF1 such as farnesyl transferase inhibitors, statins or rapamycin. Construction of the visual learning apparatus is in progress.