Tics in patients with Tourette syndrome (TS) are thought to reflect hyperactivity of the direct-pathway of the basal ganglia. The activity of direct-pathway Medium Spiny Neurons (MSNs) in the striatum is highly controlled by feedforward inhibition from local fast-spiking (FS) interneurons. To study the role of feedforward inhibition in controlling basal ganglia output, we will selectively decrease activity of FS interneurons in both acute brain slices and in vivo using a compound called philanthotoxin (Phtx). Phtx blocks Ca2+-permeable AMPA receptors which are abundant at excitatory synapses onto FS interneurons but not other classes of striatal neurons. In acute brain slices, Phtx reduces excitatory postsynaptic currents (EPSCs) evoked by intrastriatal stimulation in FS interneurons by 75% but does not affect EPSCs in MSNs. To validate the use of Phtx as a tool to selectively reduce feedforward inhibition in vivo, the firing rates of MSNs in response to cortical stimulation will be recorded in anesthetized mice before and after infusion of Phtx into the striatum through a fluid port mounted to the recording electrode. To test the hypothesis that reduced feed- forward inhibition leads to hyperactivation of the direct-pathway and concomitant increases in repetitive motor behavior, we will monitor behavior before and after bilateral infusion of Phtx through cannulas surgically implanted over dorsolateral striatum. Locomotion will be assessed by monitoring the animal’s average velocity, number of movement bouts, bout length, and time spent freezing. Other aspects of behavior that will be analyzed are: gnawing, grooming, jumping, circling and taffy pulling, all behaviors that are altered in animal models of Tourette syndrome or the closely related Obsessive Compulsive Disorder (OCD). These experiments will provide insights into the role of FS interneurons in normal striatal function and could establish FS interneurons as important therapeutic targets in TS and other basal ganglia disorders. Aryn H. Gittis, Ph.D., Anatol C. Kreitzer, Ph.D. University of California, San Francisco, CA. Award: $29,326 Commentary: Tics in patients with Tourette syndrome (TS) arise from dysfunction of the basal ganglia, a brain region critical for motor function. While we know that a part of the basal ganglia called the striatum has fewer fast-spiking nerve cells in people with TS, the functional relevance of this is not understood. Here, we propose experiments to selectively reduce the activity of these fast-spiking nerve cells in the striatum of awake mice so that we can determine what effect this has on motor function. These experiments may yield insights into mechanisms of basal ganglia dysfunction in patients with TS. Tourette Association of America Inc. – Research Grant Award 2010-2011