While the pathophysiology of Tourette Syndrome (TS) is not fully understood, the dysfunction of multiple neurotransmitter systems in contrico-basal ganglia-thalamo-cortical circuitry is thought to underlie the disorder. A prevailing hypothesis of TS pathophysiology postulates an excessive nigrostriatal dopaminergic activity, which is consistent with empirical evidence from clinical studies. The current pharmacological treatment for TS includes antipsychotics such as dopamine receptor antagonists. However, these compounds are commonly associated with severe adverse effects. There is a dire need to develop novel strategies for treatment of this disorder that are devoid of severe adverse effects. In addition to the hyperdopaminergic activity in the striatum, anatomical, neuroimaging and electrophysiology studies in TS patients have revealed a decreased number of striatal cholinergic and GABAergic interneurons and increased neuronal activity in the cortex and thalamus, which provide excitatory glutamatergic input to the striatum. This leads to the proposal that excessive corticostriatal and thalamostriatal activity might also contribute to the hyperkinetic disorder associated with TS. Thus, suppression of the increased corticostriatal and thalamostriatal glutamatergic transmission might have potential therapeutic benefit for treatment of TS. Dopamine release and glutamatergic synaptic transmission are highly regulated by multiple neuronmodulators, including acetylcholine. We recently developed a series of novel positive allosteric modulators (PAMs) that are highly selective for subtype 4 muscarinic acetylcholine receptors (M4 mAChRs). M4 mAChRs are abundantly expressed in the striatum and have been implicated in modulation of dopaminergic function and glutamatergic transmission. The goals of this proposed study are to: 1. Test the hypothesis that M4 PAMs reduce DA release in the striatum. 2. Test the hypothesis that activation of M4 mAChRs reduces glutamatergic transmission at corticostriatal and thalamotriatal synapses in striatal projection neurons. 3. Determine the ability of M4 PAMs to restore the behavioral abnormality in an animal that resembles dopaminergic dysfunction associated with TS. Zixiu Xiang, Ph.D. & Peter Conn, Ph.D. Vanderbilt University Medical Center, Nashville, TN Award: $150,000 Tourette Association of America Inc. – Research Grant Award 2013-2014