A Celsr3 Mutation Linked to Tourette Disorder Disrupts Cortical Dendritic Patterning and Striatal Cholinergic Interneuron Excitability

Tourette Disorder (TD) is a prevalent neurodevelopmental condition characterized by chronic motor and vocal tics. A mechanistic understanding of both the genetic etiology and brain pathophysiology remains poor. To gain insight into the molecular underpinnings of TD, we have generated a novel mouse model expressing an orthologous human mutation in <i>CELSR3</i>, a high-confidence TD risk gene. This putative damaging de novo variant, R774H, causes an amino acid substitution within the fifth cadherin repeat. Unlike previous <i>Celsr3</i> TD models and <i>Celsr3</i> constitutive null mice, mice homozygous for the R774H amino acid substitution are viable. They have grossly normal forebrain development and no changes to the density of cortical and striatal interneuron subpopulations. However, 3D geometric analysis of cortical pyramidal neurons revealed changes to dendritic patterning and the types and distributions of spines. Furthermore, patch clamp recordings in cholinergic interneurons located within the sensorimotor striatum uncovered mild intrinsic hyperexcitability and changes to spine density. Despite these changes, <i>Celsr3^R774H</i> homozygous mice do not show repetitive motor behaviors at baseline nor motor learning impairments. However, <i>Celsr3^R774H</i> homozygous males have sensorimotor gating deficits, a behavioral phenotype observed in both humans with TD and previously reported mouse models. Our findings suggest human mutations in CELSR3 may affect dendritic patterning, spine formation and/or turnover, and the firing properties of neurons within cortico-striatal circuits.