CELSR3 deficiency leads to tic-related behaviors and dopaminergic alterations in the striatum

Abstract

AbstractThe geneCELSR3(cadherin EGF LAG seven-pass-G-type receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS) Here, we characterized the behavioral phenotypes ofCelsr3mutant mice to verify whether the deficiency of this gene is associated with TS predisposition.Celsr3mutant mice displayed tic-like grooming stereotypies and jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Single-nucleus transcriptomic analyses revealed thatCelsr3mutants featured a unique group of eccentric striatal projection neurons. Notably, theDrd3gene, encoding the dopamine D3 receptor, was significantly upregulated in these cells as well as striosomal D1-positive neurons, while it was reduced in calretinin-positive GABAergic interneurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypiesin Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution across various striatal cell populations contribute to the tic-like responses associated withCelsr3deficiency.