Substrates Regulating Basal Ganglia Circuit Formation and Motor Stereotypy

Grant Type
Grant Year
Institution Location
Institution Organization Name
Georgetown Univ.
Investigators Name
Kromer, Lawrence, PhD

Although the etiology of the 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 striatum of the brain are known to be associated with TS. In addition, it is known that pharmacological agents that reduce dopamine transmission can ameliorate tic severity associated with TS, whereas psycho-stimulants that elevate dopamine, exacerbate tic expression. Our hypothesis for this study is that subtle changes in the expression and/or distribution of axonal guidance molecules, that regulate the proper formation of corticostriatal and dopamine circuits during development may contribute to the etiology of TS. Ephrins and their cognate Eph receptors represent one family of axon guidance molecules that are highly expressed in areas of the brain where dopamine neurons are located. Because the prefrontal cortex-striatal circuit is strongly implicated in regulating motor stereotypies, such as tics in TS, one aim of my research is to investigate whether deletions of specific members of the Eph/ephrin family disrupt the normal topographic organization of prefrontal cortical projection to the striatum. If alterations in the corticostriatal projections are observed, we will determine whether there is any association with the presence of spontaneous and stress-induced stereotypic motor behaviors. A second aspect of this project is to determine whether dopamine projections to the prefrontal cortex and/or striatum are altered in mice with deletion of specific ephrins and Eph receptors. Any changes in the organization of dopamine projections will be correlated with the severityof dopamine agonist-induced stereotypies. It is my hope that information obtained from these studies may provide important insight into whether disruptions in the normal pattern of Eph/ephrin expression in the cortex, striatum, or ventral midbrain alters the organization or function of synaptic circuits in these regions and produce stereotypic motor behaviors. Results from these studies may provide a biological basis for understanding how genetic and environmental factors that alter the expression of axonal guidance molecules during critical periods of neurodevelopment may result in aberrant striatal circuits leading to the expression of tics or obsessive-compulsive behaviors observed in TS. Lawrence F. Kromer, Ph.D. Georgetown Univ. Medical Center, Washington, D.C. Award: $50,000 Tourette Association of America Inc. – Research Grant Award 2008-2009