Examining the Role of the Cerebellum and Cerebello-Basal Ganglia Interactions in Dystonia
Fremont, Rachel Theahaya
MetadataShow full item record
Dystonia is a devastating movement disorder for which the etiology is poorly. understood. Recently, a pharmacologic rodent model of the inherited dystonia Rapid Onset Dystonia-Parkinsonism (DYT12) was generated which faithfully recapitulated the disorder. DYT12 is associated with loss-of-function mutations in the alpha3 isoform of the sodium-potassium ATPase (sodium pump). The model demonstrated that partially blocking sodium pumps in the cerebellum was necessary and sufficient to induce dystonia in rodents. We find that partially blocking sodium pumps in the cerebellum results in abnormal activity of Purkinje cells and neurons of the deep cerebellar nuclei which comprise the primary output of the cerebellum. Silencing activity in the cerebellum alleviates dystonia. Transmission of this abnormal activity to the basal ganglia via a di-synaptic pathway is important in this model, because severing the pathway alleviates dystonic symptoms. Further, dystonia due to partially blocking sodium pumps in the cerebellum is associated with altered activity in the basal ganglia. Because of the success of the pharmacologic model, we next tested whether acute knockdown of the alpha3 isoform of the sodium pump in different brain regions could recapitulate aspects of DYT12. We found that knockdown in the substantia nigra resulted in Parkinsonism while knockdown in the cerebellum caused dystonia. We then determined whether the cerebellum could contribute to other hereditary dystonias due to loss-of-function mutations. To do this, shRNA was used to knockdown the causative protein in the cerebellum and other regions of the brain. Cerebellar knockdown of the causative protein in DYT1 resulted in dystonia. Our findings suggest that the cerebellum likely contributes to symptoms in some inherited dystonias.