Fragile X syndrome is widely acknowledged as the most common form of inherited mental retardation (MR). Individuals with this disorder have several physical and behavioral abnormalities including typical facial features, macroorchadism, and mental retardation. What is often less appreciated, but which may be more critical to the overall quality of life is the fact that individuals with fragile X are hyperactive and hyperaroused, and have increased anxiety especially in social situations. These latter behavioral abnormalities are the focus of the present project.
We believe that this project will be the first attempt to understand the role of FMRP in several behavioral responses, which are often ignored by the scientific community, but which are critical to the overall quality of daily life for individuals with fragile X syndrome and their families.
In aim 1 we will dissect the exploratory activity and anxiety-related phenotypes in Fmr1 KO and Fmr1 overexpressing mice. We will design a series of behavioral experiments to test the hypothesis that Fmr1 KO mice are hyperactive, and have increased anxiety, but the anxiety phenotype is determined by the test situation.
Aim 2 will determine if Fmr1 KO mice have altered social behaviors. We believe that the Fmr1 KO mice are socially submissive, and will display less social interactions than wild-type mice.
Aim 3 will simultaneously assess behavioral and physiological responses of Fmr1 KO mice. We seek to determine if the abnormal behavioral responses of Fmr1 KO mice are paralleled by abnormal physiological responses. Radio telemetry will assess both basal physiological responses and physiological responses during different behavioral tests.
Aim 4 will determine whether we can use pharmacological interventions to alter the abnormal behavioral phenotypes of Fmr1 KO mice. There are currently no drugs specifically developed to treat the various abnormal behavioral responses of fragile X syndrome. We plan to evaluate the potential for using the Fmr1 KO mouse as a model system for identifying different drugs that may be efficacious in fragile X.
We believe that our use of these mutant mouse models will provide crucial insights into FXS, and will be an invaluable tool for the research community to refine existing therapeutic treatments as well as develop new interventions.

Relevance of the project to MRDDRC Mission:
The current project seeks to better understand the role of FMRP in a mouse model of mental retardation, and to begin to use the mouse model to identify new therapeutic interventions.