This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Fragile X syndrome is the leading known genetic cause of mental retardation in the United States. This proposed research addresses how dopamine release and uptake alterations, measured in the striatum of the Fmr1 KO mouse model of fragile X syndrome, impact behaviors associated with the disorder. The central hypothesis for this proposed research, based on compelling preliminary data and other studies, is that vesicular dopamine release is impaired in the Fmr1 KO striatum. To test this hypothesis, two specific aims will be pursued: 1) identify the impact of amphetamine, which causes the efflux of dopamine and other biogenic amines, on electrically-stimulated dopamine release and uptake in brain slices from Fmr1 KO and wild-type control mice and 2) determine the ability of amphetamine to induce focused stereotypies and other behaviors in Fmr1 KO and wild-type control mice. Fast-scan cyclic voltammetry will be used to measure dopamine release and uptake in striatal brain slices from Fmr1 KO and control mice on near-millisecond timescales with and without amphetamine. Force-plate actometer measurements will be obtained at a sampling rate of 50 measurements per second to quantitatively measure behavioral features of Fmr1 KO and WT mice before and after amphetamine injection. Meeting the objectives of these specific aims will provide insight into the neurochemical alterations occurring in the Fmr1 KO striatum and the impact of these alterations on behavioral features unique to fragile X syndrome and autism. Thus, this proposed research will: 1) lay the foundation for future studies directed toward understanding the intracellular mechanisms responsible for dopamine release alterations and 2) provide knowledge needed to develop pharmacological strategies for the treatment of fragile X syndrome.
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