The overall hypothesis of this rograin project is that progressively severe dopaminergic deafferentation of the striatum that occurs as Parkinson's Disease (PD) advances leads to unopposed glutatmatergic excitation on the spines of medium spiny neurons, ultimately causing degeneration of these structures. Our long-term goal is to determine the mechanisms that underlie this secondary generation in MSN spines in PD, new knowledge that may be useful in understanding and ultimately effectively treating the altered pharmacologic responses that complicate management of advancing PD. In Project 4, we propose to test this hypothesis by performing a comprehensive biochemical, ultra structural, and morphologic examination of MSN spines in tissue obtained by rapid autopsy (post-mortem interval less than 5 hr) from volunteers who died with PD, Dementia, with Lewy Bodies (a similar but less severe form of mesostriatal dopaminergic deafferenation), and age-matched controls, and to correlate these biochemical and structural changes with eachother and the clinical characteristics of each patient's movement disorder and response to therapy.
The specific aims for Project 4:
Aim 1 will be to determine ultrastructural features of MSN spine excitatory input onto MSNs spine heads and shafts in different regions of human striatum and to compare these with rats following unilateral dopaminergic deafferentation with 6-hydroxydopamine (6-OHDA), Aim 2 will be to determine the relative concentrations of protein elements of the glutamate receptor complexes, and Aim 3 will be to determine MSN spine degeneration by measuring striatal regional MSN spine density using Golgi silver impregnation and quantitative imaging.
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