Restless legs syndrome (RLS) is a chronic sleep motor disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move them for relief. Past pathophysiological studies have associated RLS to the disorder of the central dopaminergic system and iron metabolism. Family and twin studies strongly support a genetic contribution to the pathogenesis of RLS. Tremendous progress has been made recently of uncovering genes linked to RLS. Three independent studies published in the last two years all pointed to the role of BTBD9 in RLS. The function of BTBD9 protein is not known. Current animal models include 6-hydroxydopamine-lesioned rodents, iron deficiency mice, and dopamine receptor 3 knockout mice. The identification of the RLS genes paves the way for making genotypic model of RLS that will be more relevant in elucidating the pathophysiology of RLS and developing therapeutic treatments. The broad, long- term objective of our research is to use both complete and targeted conditional knockout mice to determine: 1) the function of the BTBD9 protein in vivo, and 2) how mutations in the BTBD9 protein can lead to RLS. The specific goal of this application is to generate conditional Btbd9 knockout mice and to use our previously generated complete Btbd9 knockout mice to answer these questions. We hypothesize that that different body regions contribute differently to the pathophysiology and symptomology of RLS. We further hypothesize that mutations in BTBD9 lead to alterations in the central dopaminergic system, in particular the striatal D2 receptor mediated indirect pathway. In turn these striatal alterations will affect plasticity in the basal ganglia, in particuar the striatum and, through intrinsic and downstream effects, other regions such as the spinal cord, leading to unpleasant sensations, an urge to move, and other RLS-like phenotypes. We plan to test our hypothesis with the following Specific Aims. 1) To test the hypothesis that functional alterations in the central nervous system underlie the pathophysiology of RLS, we will generate conditional knockout mice of Btbd9 and analyze for RLS-like behavioral and molecular phenotypes. 2) To test the hypothesis that loss of Btbd9 disrupts the dopaminergic system, we will use Btbd9 complete knockout mice and mice with Btbd9 conditionally knocked out in dopaminergic neurons only, and conduct an extensive and thorough analysis of the dopaminergic system in the striatum and spinal cord. 3) To test the hypothesis that loss of Btbd9 alters neural plasticity in basal ganglia circuitry and the spinal cord, we will perform electrophysiological recordings of the corticostriatal tract of the brain and lumbar section of the spinal cord. The successful completion of the above Specific Aims will help us to determine the function of BTBD9 protein in vivo and how the mutation of BTBD9 causes RLS. The results should significantly increase our understanding of the pathophysiology of RLS, which can ultimately aid the development of therapeutic treatments for RLS patients.
The successful completion of the proposed research project will help us to determine the function of BTBD9 protein and how the mutation of BTBD9 gene causes Restless Legs Syndrome. The results should ultimately aid the development of therapeutic treatments for Restless Legs Syndrome patients.
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