Physiology of Dystonia: Animal Studies

Dystonia is currently ranked as the third most prevalent motor disorder. It is typically characterized by involuntary muscle over- or co-contractions that can cause painful abnormal postures and jerky movements. Dystonia is a heterogenous disorder-across patients, dystonic symptoms vary in their severity, body distribution, temporal pattern, onset, and progression. There are also a growing number of genes that are associated with hereditary dystonia. In addition, multiple brain regions are associated with dystonic symptoms in both genetic and sporadic forms of the disease. The heterogeneity of dystonia has made it difficult to fully understand its underlying pathophysiology. However, the use of animal models has been used to uncover the complex circuit mechanisms that lead to dystonic behaviors. Here, we summarize findings from animal models harboring mutations in dystonia-associated genes and phenotypic animal models with overt dystonic motor signs resulting from spontaneous mutations, neural circuit perturbations, or pharmacological manipulations. Taken together, an emerging picture depicts dystonia as a result of brain-wide network dysfunction driven by basal ganglia and cerebellar dysfunction. In the basal ganglia, changes in dopaminergic, serotonergic, noradrenergic, and cholinergic signaling are found across different animal models. In the cerebellum, abnormal burst firing activity is observed in multiple dystonia models. We are now beginning to unveil the extent to which these structures mechanistically interact with each other. Such mechanisms inspire the use of pre-clinical animal models that will be used to design new therapies including drug treatments and brain stimulation.