Tourette Syndrome (TS) is thought to result from aberrant development of cortico-basal ganglia circuits of the brain, and is likely to involve prenatal factors in combination with a genetic predisposition. The main input station of the basal ganglia, the striatum, is an anatomically heterogeneous structure that receives massive inputs from both the cortex and substantia nigra. Striatal output neurons are segregated into ‘patch’ (or ‘striosome’) and ‘matrix’ compartments on the basis of phenotype as well as both afferent and efferent connections. Because the patterns formed are critical to information flow through the striatum, it is important to understand the factors guiding the development of this compartmentalization. We have developed an organotypic culture preparation that enables the study of specific factors directing pattern formation and the development of circuitry in the cortico-basal-ganglia system. Striatal slices taken from perinatal rats, either prior to or after in vivo patch/ matrix formation, are grown in the presence of cortex and substantia nigra. First, using cortex derived from yellow fluorescent protein (YFP) mice, in combination with immunohistochemical and tract-tracing techniques, we will reveal the topography of corticostriatal and nigrostriatal ingrowth in relation to the developing patch/matrix compartments. Our specific hypothesis here is that patches are formed at sites of correspondence of corticostriatal and nigrostriatal afferents. In the second part of this project, we will perturb development by interfering with cell proliferation at a critical prenatal age, in order to mimic one possible consequence of prenatal exposure to drugs, hypoxia, or infectious agents. To do this, we will administer the antimitotic agent methylazoxymethanol at a critical gestational age in the rat, and study patch formation and afferent ingrowth in slices prepared from these fetuses. We hypothesize that interference with the precise timing of maturational events will disrupt pattern formation and development of neural circuitry, leading to lasting changes in the function of this system. The proposed studies will provide a framework to investigate the sequence of developmental disruptive events that contribute to the pathophysiology of TS. The overall goal of this study will be to understand how a discrete developmental insult—which could result from prenatal drug exposure, infection, or hypoxia—acts to disrupt the timing of neuron generation and afferent ingrowth thereby producing long-lasting disruption of circuitry in cortico-basal ganglia loops. Hopefully, knowledge of the precise developmental factors that interact in the development of patterns in these structures will allow us to develop the means of intervening in situations resulting in abnormal brain development, thus possibly preventing the emergence of TS symptoms. Abigail Snyder-Keller, Ph.D., Research Scientist, State of New York, Department of Health, Biggs Laboratories, Albany, NY Award: $72,553 Tourette Association of America Inc. – Research Grant Award 2002-2003