37.5 PATHOPHYSIOLOGICALLY GROUNDED MODELS OF TIC DISORDERS: HISTAMINE DYSREGULATION IN TOURETTE'S DISORDER

Objectives: TD and related tic disorders remain enigmatic, and their pathophysiology remains obscure. Pathophysiologically grounded animal models will be informative in clarifying the nature TD and related conditions and in lighting the way to new treatments, but such models have been difficult to develop. Methods: We have recapitulated a rare but high-penetrance TD-associated mutation in the histidine decarboxylase (Hdc) gene as the basis for such a model. Results: We found disruption of Hdc, which is required for the biosynthesis of histamine (HA), to produce abnormalities in dopamine modulation of the basal ganglia and to predispose animals to develop tic-like stereotypies. More recently, we have used more specific disruption or chemogenetic regulation of histaminergic neurons, which are found in the posterior hypothalamus, to establish that this effect is dependent on neuronal and not peripheral HA and that HA modulation of the basal ganglia is both necessary and sufficient for the production of repetitive behavioral pathology. Conclusions: These findings provide us with a particularly well-grounded model in which to study the pathophysiology of tic disorders and hold great promise for the development of new therapeutic strategies.