Typically, the development of animal models has been a key step in discovering the mechanisms of complex diseases, thus paving the road to new therapies. Because of the complex nature of Tourette Syndrome and its symptoms the development of animal models for this disorder has been challenging. Though animals sometimes engage in repetitive behaviors, it is impossible to determine whether these behaviors represent tics or some other sort of repetitive act. One way to develop a model of TS in an animal is to recapitulate in the animal some genetic, molecular, or neuronal alteration found in the brains of people with TS. Until recently this has been impossible. A TSA-funded study recently performed at Yale University has revealed that a particular type of interneuron, the fast-spiking interneuron, is reduced in number in the brains of patients with severe, treatment-resistant Tourette Syndrome. These interneurons are thought to play a critical role in regulating the passage of information through the striatum by associating sensory cues – sounds, touches, sights – with motor actions. When that regulatory function is disrupted, sensory-motor associations are likely to become disorganized, and this may be the neurobiological origin of tics. The aim of this study is to recapitulate this regulatory disruption in an animal model by producing genetically altered mice in which the fast-spiking interneurons in the striatum can be selectively altered or eliminated. Observing the behavioral consequences of such a disruption will help us understand the role of the interneurons and the impact of their reduced number in causing TS. These animals may provide a fruitful model in which to try out new therapeutic strategies. For technical reasons, producing a specific disruption of the striatal fast-spiking interneurons in a mouse is difficult. As a first step, we are developing and optimizing the necessary techniques to specifically manipulate or eliminate interneurons in the striatum. Once this is accomplished, we will examine the resulting mice performing behavioral tests that probe the function of the striatum. By creating animal models that closely recapitulate the differences seen in the brains of people with TS, we hope to create new opportunities for the development of future drug therapies. Christopher Pittenger, M.D., Ph.D. Yale University Clinical Neuroscience Institute, New Haven, CT Award: $74,876 (2nd Year) Tourette Association of America Inc. – Research Grant Award 2008-2009