The neural substrates of Rapid-Onset Dystonia-Parkinsonism

Although dystonias are a common group of movement disorders the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected subjects can be symptom free for years but rapidly develop persistent dystonia and parkinsonism-like symptoms after a stressful experience. Using a mouse model here we show that an adverse interaction between the cerebellum and basal ganglia can account for the symptoms of the patients. The primary instigator of dystonia is the cerebellum whose aberrant activity alters basal ganglia function which in turn causes dystonia. This adverse interaction between the cerebellum and basal ganglia is mediated through a di-synaptic thalamic pathway which when severed is effective in alleviating dystonia. Our results provide a unifying hypothesis for the involvement of cerebellum and basal ganglia in generation of dystonia and suggest therapeutic strategies for the treatment of RDP.