Control of Cortical Inputs to the Ventral striatum by Dopamine and Local Inhibition: Effects on Weak and Strong Inputs (2nd year)

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Maryland
Investigators Name
Gruber, Aaron, PhD

The age of onset of Tourette Syndrome (TS) is concurrent with the formation of neural circuitry and synapses in the developing brain. Individuals with TS have an altered distribution of parvalbumin- expressing GABAergic interneurons (a unique nerve cell type) in the basal ganglia. The majority of forebrain GABAergic interneurons come from the ganglionic eminence which is the embryonic precursor of the basal ganglia. The abnormal distribution of these cells suggests that TS may be due to a disruption in neuronal development. The syndrome’s underlying genetic mechanisms are complex and multiple genes are probably involved. Genetic linkage studies suggest that genes located on chromosomes 5, 7, 10, and 12 may be involved. The susceptibility region on chromosome 7 has been narrowed to 7q31, which is the location for the MET gene (crucial for proper formation of cortical and striatal GABAergic interneurons). MET is a tyrosine kinase that can regulate many biological functions, including cell proliferation and differentiation. Our data demonstrate that genetic deletion of MET in the developing mouse basal ganglia greatly reduces the number of parvalbumin neurons in the adult striatum. Thus, mutations in the MET gene may contribute to TS. We propose to examine how MET signals GABA- ergic interneuron migration in the developing basal ganglia and overlying cortex. We will examine cell fate in MET mutant mice using birthdating labeling followed by immunohistochemistry in the adult for parvalbumin-expression. We will also use an organotypic culture preparation to study rates and destinations of neuronal migration in the developing ganglionic eminence of MET mutant mice. These studies will reveal the molecular mechanism responsible for the development of the parvalbumin GABAergic interneurons and help to determine whether MET is a candidate mediator of TS. Aaron J. Gruber, Ph.D. University of Maryland School of Medicine, Baltimore, Maryland Award: $33,000 (2nd Year) Tourette Association of America Inc. – Research Grant Award 2006-2007