It has been shown that mutations in a gene called SLITRK1 are associated with Tourette Syndrome (TS), Obsessive- Compulsive Disorder (OCD) and trichotillomania in some families. In an animal model, mice with a disruption of this same gene demonstrated that increased anxiety behaviors could be reversed by clonidine, an alpha2-adrenergic agonist that is used to treat some symptoms of TS. Thus, although somewhat controversial, SLITRK1 remains an interesting candidate gene for TS and related disorders and examination of SLITRK1 mutations, while likely not a common cause of TS, may yield important information about the pathophysiology of TS. SLITRK1 is known to regulate neurite growth. Our lab is interested in the role of SLITRK1 in the developing nervous system. We have focused on identifying how SLITRK1 is processed in the cell and how its function is regulated by cellular mechanisms. For example, phosphorylation appears to regulate the interaction of SLITRK1 with other proteins. In addition, we are characterizing the extracellular and intracellular cleavage products of SLITRK1 to understand more about their function and regulation. We have observed that the SLITRK1 intracellular domain interacts with 14-3-3 proteins and that this is also a regulated interaction. This year we will continue with our cell biology studies of SLITRK1, generate a mouse model of a SLITRK1 mutation associated with TS and examine 14-3-3 as another candidate gene for TS and related disorders. Dorothy E. Grice, M.D., Joseph Buxbaum, Ph.D. New York State Psychiatric Institute & Columbia University New York, NY Award: $74,900 (2nd Year) Commentary: Several years ago, researchers discovered that changes in a particular gene (SLITRK1) might be the cause of TS in some people. In this study Drs. Grice and Buxbaum will study the same gene to get a better understanding of how it normally works in cells in the body. This work will allow scientists to know how and why changes in the SLITRK1 gene might cause changes in the brain and lead to the development of TS. The investigators are also proposing to create mice with TS-like behaviors by changing their genes. This mouse model could be useful for developing and testing therapies for people with TS. Tourette Association of America Inc. – Research Grant Award 2009-2010