Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice

Dystonia is common, debilitating, often medically refractory, and difficult to diagnose. The gold standard for both clinical and mouse model dystonia evaluation is subjective assessment, ideally by expert consensus. However, this subjectivity makes translational quantification of clinically-relevant dystonia metrics across species nearly impossible. Many mouse models of genetic dystonias display abnormal striatal cholinergic interneuron excitation, but few display subjectively dystonic features. Therefore, whether striatal cholinergic interneuron pathology causes dystonia remains unknown. To address these critical limitations, we first demonstrate that objectively quantifiable leg adduction variability correlates with leg dystonia severity in people. We then show that chemogenetic excitation of striatal cholinergic interneurons in mice causes comparable leg adduction variability in mice. This clinically-relevant dystonic behavior in mice does not occur with acute excitation, but rather develops after 14 days of ongoing striatal cholinergic interneuron excitation. This requirement for prolonged excitation recapitulates the clinically observed phenomena of a delay between an inciting brain injury and subsequent dystonia manifestation and demonstrates a causative link between chronic striatal cholinergic interneuron excitation and clinically-relevant dystonic behavior in mice. Therefore, these results support targeting striatal ChIs for dystonia drug development and suggests early treatment in the window following injury but prior to dystonia onset. One Sentence Summary Chronic excitation of dorsal striatal cholinergic interneuron causes clinically-relevant dystonic phenotypes in mice