Microsoft word - galter role of l-dopa treatment etc in mitopark mice.doc
Application form new project Project title: What is the role of the L-DOPA treatment induced, striatal TH in the development of stereotypic / dyskinetic behavior in MitoPark mice?
Project Leader: Dagmar Galter
Collaborators: Lars Olson
Aim: The aims of the project are to characterize these ectopic TH-immunoreactive cells in human and mouse tissue and to investigate the potential role of these cells in the development of stereotypic / dyskinetic behavior. Are they markers of dyskinesia? Project description: We found that the ectopic expression of TH mRNA and protein expression in striatum of MitoPark mice is age-dependent and is increasing with the dopamine depletion in the brain. Furthermore is the number of TH cells dependent on the amount of L-DOPA given as daily treatment for 10 to 21 days. Cells expressing TH have also been identified in the striatum of Parkinson patients. We plan to characterize this cell population and compare it to other neurons in the striatum using double immunohistochemistry with markers of subpopulations of medium spiny neurons. Today it is not clear if they can produce dopamine (DA) and if toy use it as neurotransmitter. To study the electrical properties of these cells and analyze if they are integrated in the striatal we plan to crossbreed MitoPark with TH-EGFP mice in order to identify L-DOPA-induce TH cells in vivo. In addition we will analyze if the induction of these cells is related to stereotypic and dyskinetic behavior. Today only unilateral animal models are used to study L-DOPA induced dyskinesia (LID), models based on toxin induced DA depletion. One advantage of unilateral models is the well-characterized and accepted rating scale based on unilateral movements of the animals. On the other hand does this unilateral development of symptoms not match dyskinesia in PD patients, which in the vast majority of the cases is bilateral. There is also the risk that the contralateral striatum side, witch is not DA depleted and mostly used as “the control side”, is actually involved in compensatory effects, which mask the molecular and cellular changes induced by the treatment. A further drawback of these models is the variability in the toxin delivery, which is avoided in a genetic PD model. We will therefor investigate if it is possible to establish MitoPark mice as a bilateral dyskinesia model. We will analyze behavior and cellular markers of LID such as FosB induction, increase in pro-pre- enkephaline and prodynorphine mRNA. Finally we will determine if the induction of TH-ir cells and LID can be prevented by anti-dyskinesia treatments. We plan to test if well-known anti-dyskinetic treatments, such as amantadine, can prevent the induction of these TH neurons in MitoPark mice. The identification of reliable cellular markers for the L-DOPA induced side effects and the development of a suitable genetic animal model will be an important step in the improvement of drug treatments for PD. Findings in the planed study will be a basis for further development of therapies with fewer side effects. Request for personnel: Funding for a Postdoc researcher is requested.
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