Dopaminergic Control of GAD Gene Expression in the Basal Ganglia

Grant Type
Grant Year
Institution Location
Institution Organization Name
Medical College of Pennsylvania
Investigators Name
Chesselet, M.F., MD, PhD

The neurotransmitter dopamine is believed to play a critical role in the generation of symptoms in Tourette Syndrome. One area of the brain where abnormal dopaminergic neurotransmission may occur in this disorder is the striatum, an area of the brain which is stimulated by dopaminergic neurons and is involved in both cognitive and motor behavior. The output of the striatum consists of a succession of neurons using the inhibitory neurotransmitter GABA and influencing motor control by other brain areas. Little is known about the effect of dopamine and of chronic alteration of dopaminergic neurotransmission on those GABA-ergic neurons. Our hypothesis is that alteration of dopaminergic neurotransmission in the striatum results in changes in the level of expression of the gene entoding glutamic acid decarboxylase (GAD) the enzyme responsible for the synthesis of GABA in neurons of the striatum and of its target areas. This could lead to chronic alterations of GABA-ergic neurotransmission in these neurons and occur in Tourette Syndrome. In this study, we will measure the level of messenger RNA for GAD in neurons of the striatum and of its two main target areas, the pallidum and the striatum and of its two main target areas, the pallidum and the substantia nigra after lesions of dopaminergic neurons and injections of agonists and antagonists of dopaminergic receptors. This will be done by in situ hybridization histochemistry, a method which allows for the detection of specific messenger RNA in the individual neurons and, therefore, will allow us to study the topographical specificity of these effects. The effect of drugs acting specifically on subpopulations of dopaminergic receptors (D1 or D2) will also be examined. This may provide valuable information for the use of these agents in the treatment of Tourette Syndrome and, help us to gain a better understanding of the pathophysiology of the ailment. M. F. Chesselet, MD, Ph.D. Medical College of Pennsylvania, Philadelphia, PA Award: $24,983 Tourette Association of America, Inc. – Research Grant Award 1988