SP7: Systemphysiologie der Dystonie in DYT1- und DYT12- Nagetiermodellen
- deutscher Text in Kürze -
Projektleitung: Chi Wang Ip
Partner: Ioannis Isaias
Partner: René Reese
Pathophysiology of dystonia, a genetically heterogeneous disease with similar clinical features is still unclear. Environmental factors as trigger for dystonia in susceptible subjects have been discussed but there is still a lack of evidence (“second hit”). For primary dystonia animal models with dystonic phenotype are rare or lacking. The main goals of our project are
1.) to establish 2 models of primary dystonia in rats (transgenic DYT1, pharmacological DYT12) that show a dyst onic phenotype after induction of sensory stress, to prove the “second hit” hypothesis. To this end we are going to induce sensory stress (sciatic nerve crush). Dystonia will be scored clinically (gait analysis, rotarod test) and by dual channel electromyography recordings.
2.) To investigate the pathophysiology of dystonia in these 2 models comparing dystonic with non-dystonic animals focusing on the CNS dopaminergic neurotransmission by Western blot and mRNA analysis (Dopamine transporter, dopamine receptors), microdialysis, autoradiography and immunohistochemistry, later focus on the cholinergic, noradrenergic and serotonergic system. Micro FDG-PET will be implemented to discover regions of neuronal activity change in dystonic rats.
3.) We will perform intracerebral neuronal recordings in the entopeduncular nucleus of both dystonia rat models. This structure (human internal pallidum) shows an aberrant neuronal firing activity in dystonia patients. We aim to see similar discharge patterns of the dystonic DYT1 and DYT12 rat confirming our concept of a common final pathway leading to dystonia.
The objectives are:
- Do environmental factors trigger dystonia in genetically susceptible individuals? In a novel approach we will induce dystonia in a transgenic DYT1 and a pharmacological DYT12 rat model by applying sensory stress.
- What is the pathophysiology of dystonia? We expect to find an altered central dopaminergic neurotransmission in DYT1 and DYT12 rats once they become dystonic. Examination of cholinergic, noradrenergic and serotonergic neurotransmission will follow. Some similarities in neurotransmission are expected.
- What is the common pathway leading to dystonic phenotype in this etiologically heterogeneous disease? Intracerebral recordings of the neuronal firing pattern in the entopeduncular nucleus will be performed to find a dystonia specific pattern corresponding to altered neurotransmission as common final pathway.