Presentation Information
[SY-106-04]Modeling Genetic Heterogeneity in Tourette Syndrome: Dissecting Circuit and Behavioral Phenotypes in Mouse Models with High-Confidence Risk Mutations
*Max Tischfield1,2 (1.Rutgers University, Department of Cell Biology and Neuroscience(United States of America), 2.Child Health Institute of New Jersey, Robert Wood Johnson Medical School(United States of America))
Keywords:
Tourette Syndrome,Human Genetics,Animal Models,Behavioral phenotypes,Dopamine signaling
Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by motor and vocal tics, but its clinical manifestations extend far beyond these core symptoms. Many individuals with TS exhibit varying degrees of impulse control deficits, compulsive behaviors, and comorbid neuropsychiatric conditions such as autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD). This phenotypic heterogeneity underscores that TS exists on a spectrum, shaped by diverse genetic and neurobiological contributors. However, this complexity presents a major challenge for translational research, particularly in developing animal models that accurately recapitulate human pathophysiology. In this talk, I will present recent findings from two novel transgenic mouse lines that harbor de novo human mutations in high-confidence TS risk genes: Celsr3, the most strongly associated gene with TS identified to date, and Ank3, identified in probands with TS, OCD, and autistic features. These models display both overlapping and distinct behavioral phenotypes, including deficits in sensorimotor gating, enhanced habitual responding, and possible effects on neuromuscular control and proprioception. Notably, these models exhibit repetitive motor behaviors, but they do not fully resemble human tics. Using behavioral assays, neural recordings, and circuit-specific manipulations, we dissect how these mutations affect dopamine signaling and corticostriatal function. Our findings underscore the importance of using multiple, genetically validated models to capture the spectrum nature of TS. By examining how different mutations may perturb distinct and overlapping neural circuits, we begin to map how genetic variability gives rise to phenotypic diversity. These insights offer a framework for understanding the mechanistic basis of TS and lay the groundwork for developing targeted interventions that may include modulation of proprioceptive pathways.