Selective Knockdown of Slitrk1 Expression In Dorsal Striatum of Mice Produces Stereotypy Behaviors Mimicking Symptoms of Tourette Syndrome

Objectives: The Slitrk1 gene is one of risk genes for Tourette syndrome (TS). We aimed to investigate the role of Slitrk1 in pathogenesis of TS and validated the hypothesis that knockdown of Slitrk1 expression in striatum of mice might impair the electrophysiological function of striatal cholinergic interneurons (CINs) leading to behaviors mimicking symptoms of TS.

Methods: Slitrk1 siRNA or scramble siRNA was injected into bilateral dorsal striatum of 8-10 week-old C57Bl/ 6J mice, and we’ve conducted a serial of examinations, such as analyzing stereotypy behaviors, pre-pulse inhibition (PPI) test, electrophysiological study of striatal CINs, western blot analysis and immunofluorescent study after siRNA injection for certain days.

Results: As compared to scramble siRNA-treated group, mice treated with Slitrk1 siRNA (Slitrk1-KD) showed significantly more stereotypy behaviors, such as grooming and sniffing, which could be suppressed by haloperidol, a D2 antagonist. Slitrk1-KD mice also displayed significantly impaired PPI, one of the endophenotypes of TS. Electrophysiological study revealed striatal CINs without Slitrk1 expression showing higher action potential threshold and lower firing rate elicited by current injection. Western blot analysis and immunofluorescent study both showed decreased striatal Slitrk1 protein amount and the percentage of its colocalization with choline acetyltransferase (ChAT), the marker of CINs, especially after Slitrk1 siRNA injection for 3~7 days.

Conclusion: Our study revealed knockdown of Sltirk1 expression in striatal CINs could induce stereotypy behaviors and endophenotype of TS in mice, with electrophysiological changes in CINs as well. These results supported that Slitrk1 deficit might play some role in the pathogenesis of TS.