Cerebellar Dysfunction as a Source of Dystonic Phenotypes in Mice.

There is now a substantial amount of compelling evidence demonstrating that the cerebellum may be a central locus in dystonia pathogenesis. Studies using spontaneous genetic mutations in rats and mice, engineered genetic alleles in mice, shRNA knockdown in mice, and conditional genetic silencing of fast neurotransmission in mice have all uncovered a common set of behavioral and electrophysiological defects that point to cerebellar cortical and cerebellar nuclei dysfunction as a source of dystonic phenotypes. Here, we revisit the Ptf1a;Vglut2 mutant mouse to define fundamental phenotypes and measures that are valuable for testing the cellular, circuit, and behavioral mechanisms that drive dystonia. In this model, excitatory neurotransmission from climbing fibers is genetically eliminated and, as a consequence, Purkinje cell and cerebellar nuclei firing are altered in vivo, with a prominent and lasting irregular burst pattern of spike activity in cerebellar nuclei neurons. The resulting impact on behavior is that the mice have developmental abnormalities, including twisting of the limbs and torso. These behaviors continue into adulthood along with a tremor, which can be measured with a tremor monitor or EMG. Importantly, expression of dystonic behavior is reduced upon cerebellar-targeted deep brain stimulation. The presence of specific combinations of disease-like features and therapeutic responses could reveal the causative mechanisms of different types of dystonia and related conditions. Ultimately, an emerging theme places cerebellar dysfunction at the center of a broader dystonia brain network.