Athough the etiology of motor and vocal tics characteristic of Tourette Syndrome (TS) is not understood, abnormalities in basal ganglia anatomy and pathophysiology in the connections between the frontal cortex and the striatum are known to be associated with TS. In rodents and presumable other mammals, nerve cells in a part of the brain called the striatum are sorted into sub-compartments during the late prenatal and early postnatal periods. At present, the molecular cues that regulate this cell sorting are not known. During the initial year of TSA funding we were able to identify a family of cell surface signaling molecules called ephrins that appear to regulate the segregation of neurons into the two sub-compartments in the striatum. During the second year of TSA funding, we will determine whether disruption in the neuronal organization in the striatum affects their connection to brain cells in the cortex and whether this disruption is associated with spontaneous and stress induced stereotypic behaviors in mice. Since dysfunction in the dopamine projections to the prefrontal cortex and striatum also are reported to contribute to TS, a second component of our research during year two of TSA support is to determine whether ephrins influence dopamine innervation of the striatum or prefrontal cortex. These studies are based on the observation that enhancing dopamine function exacerbates tic severity and that ephrin receptors are expressed by dopamine neurons. Thus, the ephrin family of cell-cell signaling molecules may indirectly be implicated in controlling the severity of tic behaviors. It is my hope that results from our animal studies will enhance our understanding of biological mechanisms that might provide insight into how genes and environmental factors could alter the expression of axonal guidance molecules (such as ephrins and their receptors) during critical periods of brain development and thus, result in the aberrant organization and dysfunction of striatal circuits that regulate motor and vocal tics observed in TS. Lawrence F. Kromer, Ph.D. Georgetown University Medical Center, Washington, DC Award: $66,000 (2nd Year) Commentary: Tics are thought to occur when brain cells do not properly communicate with each other. In his previous study, Dr. Kromer showed that when the brain is being formed certain molecules are responsible for ensuring that brain cells position themselves in the correct place within a region of the brain called the striatum, which is associated with the generation of tics. In the current study, Dr. Kromer will investigate what happens when brain cells do not position themselves correctly and will see whether this displacement of the cells results in tic-like movements in laboratory mice. This study could help us understand what changes in the brain lead to the development of TS. Tourette Association of America Inc. – Research Grant Award 2009-2010