? Fragile X syndrome is one of the most commonly inherited forms of human mental retardation with an incidence rate of 1 in 4000 males and 1 in 6000 females. It is caused by the loss of FMR1 gene function. Patients with Fragile X syndrome suffer from a variety of symptoms including; mental retardation, attention deficit, hyperactivity, sleep disorders, anxiety, unstable mood and autistic-like behaviors. Physical defects include macroorchidism and irregular dendritic spine morphology. In previous studies, our lab developed a Fragile X model in Drosophila. This model is based on the dfmr1 (also called dfxr) gene, which has a high degree of sequence identity/similarity to the FMR1 gene. The dFMR1 protein has similar RNA binding properties, developmental expression pattern and subcellular distribution to the FMR1 protein (FMRP). In recent studies, we have shown that dfmr1 null mutants display several behavioral defects that bear similarity to symptoms of Fragile X patients. The relevant phenotypes in Drosophila include arrhythmic circadian behavior, attention deficit during courtship, memory defects and subtle defects of neuronal morphology. The similarities in the biochemical properties of dFMR1 and FMRP and their loss of function phenotypes suggest that these two proteins have conserved function in similar behavioral and developmental processes. Thus the Drosophila dfmr1 mutants are a relevant model to study aspects of Fragile X syndrome. To ameliorate Fragile X syndrome it is imperative that we understand when and how FMR1 activity functions to prevent cognitive and behavioral defects. The temporal requirements and molecular role of FMR1 are currently not known. We propose to use the Drosophila model of Fragile X to determine when dfmr1 activity is required to determine if the behavioral defects are due to developmental or physiological defects. We are also investigating possible physiological pathways affected by loss of dfmr1 function. Through these studies we have identified a pharmacological treatment that rescues the courtship and memory defects displayed in our dfmr1 mutants. In this proposal we will determine and verify a route of action of this drug to identify potential targets for the treatment of Fragile X syndrome. ? ?
