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

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 (Gnal+/-) mice carry a heterozygous knockout mutation of the Gnal 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, Gnal+/- 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.

Functional Alteration of Cerebello-Cerebral Coupling in an Experimental Mouse Model of Parkinson's Disease.

In Parkinson's disease, the degeneration of the midbrain dopaminergic neurons is consistently associated with modified metabolic activity in the cerebellum. Here we examined the functional reorganization taking place in the cerebello-cerebral circuit in a murine model of Parkinson's disease with 6-OHDA lesion of midbrain dopaminergic neurons. Cerebellar optogenetic stimulations evoked similar movements in control and lesioned mice, suggesting a normal coupling of cerebellum to the motor effectors after the lesion. In freely moving animals, the firing rate in the primary motor cortex was decreased after the lesion, while cerebellar nuclei neurons showed an increased firing rate. This increase may result from reduced inhibitory Purkinje cells inputs, since a population of slow and irregular Purkinje cells was observed in the cerebellar hemispheres of lesioned animals. Moreover, cerebellar stimulations generated smaller electrocortical responses in the motor cortex of lesioned animals suggesting a weaker cerebello-cerebral coupling. Overall these results indicate the presence of functional changes in the cerebello-cerebral circuit, but their ability to correct cortical dysfunction may be limited due to functional uncoupling between the cerebellum and cerebral cortex.