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

## TL;DR

A mutation in the CELSR3 gene linked to Tourette Disorder disrupts brain cell structure and function in mice, but does not cause tics.

## Contribution

A novel viable mouse model with a human CELSR3 mutation reveals specific neural changes without causing tic-like behaviors.

## Key findings

- Mice with the CELSR3 R774H mutation show altered cortical dendritic patterning and spine distribution.
- Cholinergic interneurons in the striatum of these mice exhibit mild hyperexcitability and spine density changes.
- Despite these changes, the mice do not display repetitive motor behaviors but show sensorimotor gating deficits.

## Abstract

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 CELSR3, 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 Celsr3 TD models and Celsr3 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, Celsr3R774H homozygous mice do not show repetitive motor behaviors at baseline nor motor learning impairments. However, Celsr3R774H 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.