Abnormal cerebellar signaling induces dystonia in mice

Dystonia is a relatively common neurological syndrome characterized by twisting movements or sustained abnormal postures. Although the basal ganglia have been implicated in the expression of dystonia, recent evidence suggests that abnormal cerebellar function is also involved. In these studies, a novel mouse model was developed to study the role of the cerebellum in dystonia. Microinjection of low doses of kainic acid into the cerebellar vermis of mice elicited reliable and reproducible dystonic postures of the trunk and limbs. The severity of the dystonia increased linearly with kainate dose. Kainate-induced dystonia was blocked by the glutamatergic antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide and reproduced by domoic acid microinjection, suggesting that the induction of dystonia is dependent on glutamatergic activation in this model. The abnormal movements were not associated with kainate-induced seizures, because EEG recordings showed no epileptiform activity during the dystonic events. Neuronal activation, as assessed by in situ hybridization for c-fos, revealed c-fos mRNA expression in the cerebellum, locus ceruleus, and red nucleus. In contrast, regions associated with epileptic seizures, such as the hippocampus, did not exhibit increased c-fos expression after cerebellar kainate injection. Furthermore, in transgenic mice lacking Purkinje cells, significantly less dystonia was induced after kainic acid injection, implicating Purkinje cells and the cerebellar cortex in this model of dystonia. Together, these data suggest that abnormal cerebellar signaling produces dystonia and that the cerebellum should be considered along with the basal ganglia in the pathophysiology of this movement disorder.