The mechanism by which tics are generated in the brain (pathophysiology) remains elusive. Although the exact neuroanatomic localization for tics has yet to be established, pathways that link specific regions of the frontal cortex to subcortical structures have been implicated. Within these circuits, brain chemicals (neurotransmitters) are essential for the transmission of messages between regions. To date, abnormalities of several major neurotransmitter systems including the dopaminergic, serotoninergic, GABAergic, cholinergic, noradrenergic, and opioid systems, have been hypothesized to be abnormal in Tourette Syndrome (TS). Since many neurotransmitters are interwoven in the production of complex actions, it is possible that imbalances may exist among several systems. It is also possible that problems may be associated with difficulties in the movement of neurotransmitter storage containers (vesicles) or vesicle release, i.e. synaptic vesicle docking complex. This project will investigate the underlying neuropathology of TS by use of frozen postmortem brain from 4 TS and 4 matched controls. Brain regions available for study include several components of frontal-subcortical circuits (Brodmann’s areas 6,8,9, anterior cingulate, amygdala, caudate, putamen, ventral striatum, and globus pallidus). Each region will be evaluated for several pre and post-synaptic neurochemical markers and for the synaptic vesicle docking complex by use of semi-quantitative immunoblot analyses, and HPLC measurements of amino acids, neurotransmitters, and their metabolites. An additional aim is to investigate the immune hypothesis in TS by measuring the extent of existing immune complexes in TS and control brain. This study of post mortem brain tissue will significantly enhance our knowledge of the neuropathology of Tourette Syndrome. Harvey S. Singer, M.D. Johns Hopkins University School of Medicine, Baltimore, MD Award: $45,000 Tourette Association of America Inc. – Research Grant Award 2001-2002