Tourette Syndrome (TS) and its associated conditions (tics, OCD, ADHD) constitute a substantial societal burden, as TS alone is estimated to affect nearly 1% of the population. A critical barrier to progress in understanding the mechanisms for these disorders is the lack of animal models with etiological relevance to the human condition. We propose to take advantage of the recent discovery of a genetic etiology for TS involving a nonsense mutation within the histidine decarboxylase gene to overcome this barrier. In this proposal we will create, validate and behaviorally characterize a novel mouse model for TS. To most faithfully replicate the protein-based pathobiology as it occurs in humans, we will create humanized mouse models that express the human protein in place of the endogenous mouse protein. Moreover, because such a model will express the human TS mutant protein, once validated, this mouse model will be uniquely suited for screening novel therapeutics in a way that is not afforded by conventional mouse knockin approaches.