Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D dopamine receptors.

The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D receptor, in striosomal D-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D-positive neurons. Activating and blocking D receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.