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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