Mouse and Rat Models of Dystonia

SP6: Generierung neuer Nagetiermodelle der DYT1, DYT6 und DYT25 Dystonie sowie Untersuchung des Neurotrophin (BDNF) Signalweges in diesen Modellen

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Projektleitung: Michael Sendtner

The cellular mechanisms underlying the pathophysiology of dystonia are still largely unknown. We would like to establish mouse models for TOR1A/DYT1, THAP1/DYT6, and GNAL/DYT25 to characterize histopathological, molecular and functional alterations in corticostriatal and intracortical networks. We intend to concentrate on the role of altered neurotrophin (BDNF and TrkB) signaling in the intracortical and corticostriatal networks and the consequences of such alterations for motor behavior and network functions, as described in subproject 7 and 8. In collaboration with subproject 7 we would like to study altered dopaminergic signaling and altered neuronal activity in the striatum of these mouse models and to establish new concepts how these alterations correlate with altered network activity as studied in subproject 8 and 9.

A third part of this proposal focuses on the characterization of cellular alterations in isolated cortical neurons, striatal interneurons and substantia nigra dopaminergic neurons in order to compare them with alterations studied in subproject 4 with neurons differentiated from patient-derived iPS cells.

The ultimate goal is to provide a rational basis for new disease mechanism -guided treatment strategies, by defining cellular and functional targets for new therapies.

The objectives are:

  • To breed, investigate and provide TOR1A/DYT1, THAP1/DYT6 and GNAL/DYT25 mutant mouse models and a TOR1A/DYT1 mutant rat model to this consortium
  • To characterize BDNF Trk-B signaling in these mouse models
  • To establish and characterize cell cultures from these mouse models to validate new iPS C-based models with human cells from subproject 4