Consequences of Synucleinopathy and Dopamine Depletion

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Parkinson's disease (PD) and Parkinson's-spectrum disorders produce both motor and cognitive impairments. We propose to examine behavioral disturbance of each type, impairmen t of procedural learning and development of L-dopa induced dyskinesias, and the striatal neural plasticity that may under lie them in rodent models of PD. We will combine multi-disciplinary methods that we and members of our Center have extensive experience with: behavioral observation using systematic rating scales, training on procedural tasks in a T-maze, chronic neuronal ensemble neuronal recording with tetrodes, analysis of immediate early gene expression, microarray gene assays and laser capture microscopy (collaboration With Project 4), and introduction of alpha-synuclein mutations (collaboration with Project 1 and extra-Center collaborations). We have carried out extensive preliminary studies and formed three functional Aims based on highly promising findings, in Aim 1, we propose to test whether plasticity in task-related neuronal activity in the dorsolateral striatum during a procedural learning in a T-maze will be abnormal in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions restricted to the area around the recording sites, in Aim 2, we propose to study the effects of alpha-synuclein overexpression on learning-related neuronal plasticity in the stdatum. We will use rats injected with viral vectors carrying mutant or normal forms of alpha-synuclein and engineered mice expressing alpha-synuclein mutations. Both of these Aims, animals will receive chronic intermittent L-dopa treatment either during or after acquisition of the learning task to test the effects of dopamine replacement therapy on learning and neuronal activity. In Aim 3, we propose to examine L-dopa induced dyskinesias in rats with 6-OHDA lesions. We will measure the activation of immediate early genes in the striosomes and in the matrix and will correlate the expression patterns with behavioral dyskinesias. We will also perform gene assays using laser-dissected striosome and matrix tissues to measure differential compartmental distributions of downstream genes in relation to dyskinesias. The results of these experiments will yield important knowledge about neural mechanisms underlying two forms of striatal plasticity implicated in parkinsonian syndromes: that related to procedural learning and that leading to the development of L-dopa induced dyskinesia in PD and related movement disorders.