Functional abnormalities in the cerebello-thalamic pathways in a mouse model of DYT25 dystonia.

Abstract

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia. DYT25 (<i>Gnal^+/-</i>) mice carry a heterozygous knockout mutation of the <i>Gnal</i> gene, which notably disrupts striatal function, and systemic or striatal administration of oxotremorine to these mice triggers dystonic symptoms. Our results reveal an increased cerebello-thalamic excitability in the presymptomatic state. Following the first dystonic episode, <i>Gnal^+/-</i> mice in the asymptomatic state exhibit a further increase of the cerebello-thalamo-cortical excitability, which is maintained after θ-burst stimulations of the cerebellum. When administered in the symptomatic state induced by a cholinergic activation, these stimulations decreased the cerebello-thalamic excitability and reduced dystonic symptoms. In agreement with dystonia being a multiregional circuit disorder, our results suggest that the increased cerebello-thalamic excitability constitutes an early endophenotype, and that the cerebellum is a gateway for corrective therapies via the depression of cerebello-thalamic pathways.