The striatal GABAergic microcircuitry likely plays a key role in the pathophysiology of Tourette syndrome (TS). Animal experiments have found that blockade of striatal GABA receptors provokes tic-like movements. Humans with TS have a specific deficiency in GABAergic striatal fast-spiking interneurons (FSIs), which powerfully inhibit striatal projection neurons. These data suggest that FSIs play a critical role in the pathophysiology of TS. To test this hypothesis, we will use novel optogenetic techniques to selectively silence striatal FSIs in awake, freely behaving mice. NpHR is a light activated chloride pump and neurons expressing this protein rapidly inactivate when illuminated with yellow light. We will infuse an adeno-associated virus containing the double-floxed NpHR gene into the striata of mice expressing Cre recombinase under the parvalbumin (PV, specific to FSIs in the striatum) promoter. This will lead to selective expression of NpHR in FSIs, which can then be inactivated independently of other striatal neurons. Combination fiber-optic/silicon probes will be implanted into the striatum to record electrophysiological activity during periods of FSI inactivation. The electrophysiology and optical FSI inhibition will be synchronized with video recordings to correlate behavioral with electrophysiological changes. We hypothesize that these mice will develop repetitive, stereotyped movements contra-lateral to the implant during FSI suppression. These experiments will not only investigate a key theory regarding the pathophysiology of TS, but also establish techniques to study the striatal microcircuitry in more detail. Daniel Kent Leventhal, M.D., Ph.D., Joshua Berke, Ph.D. University of Michigan School of Medicine, Ann Arbor, MI Award:$40,000 (Fellowship) Commentary: Recent evidence suggests that abnormalities of a specific type of nerve cell (“Fast Spiking Interneurons” or FSIs) in a region of the brain called the striatum, are important in the development of tic disorders. We will use novel techniques to inactivate these FSI nerve cells in normally behaving mice while recording the activity of other nearby nerve cells. We believe that inactivating the FSIs will cause specific changes in the firing patterns of neighboring nerve cells and also cause tic-like involuntary movements in the mice. If this happens then we will know that the FSI nerve cells play an important role in tic development. Tourette Association of America Inc. – Research Grant Award 2010-2011