The Role of Protein Phosphate Regulation in Dopamine Receptors Function

Grant Type
Grant Year
Institution Location
Institution Organization Name
Yale University
Investigators Name
Allen, Patrick, PhD

Current thinking about TS is that tics might represent an aberrant form of habit learning, with habits being defined as routines that link sensory Patrick Allen cues with motor action. The basal ganglia is the region of the brain that is believed to be involved in causing tics because it is this region that is intimately involved in motor learning. Specifically, the cerebral cortex sends information to the basal ganglia, where that information is processed before being relayed back to the cortex. The neurotransmitter dopamine has a profound influence on the integration of input to this neural system. Treatment of TS often involves prescribing antipsychotic drugs that block the actions of dopamine. The molecular mechanisms whereby these drugs achieve their beneficial effects are not known, but recent work has indicated that dopamine has a profound effect on a second neurotransmitter system, namely glutamate, that is important for the cortical input to the basal ganglia. Moreover, the receptors for glutamate exist on the surface of neurons in the basal ganglia, and their presence on the cell surface (hence their activity) is regulated in a dynamic manner. This project will examine the effect of dopamine on glutamate-receptor movement to the neuron surface. Within the neuron, dopamine exerts its cellular effect by activating a number of specific biochemical signaling processes including an enzyme called “protein phosphatase I”, which in turn influences the presence of the glutamate receptor on the cell surface. In this study we will examine the influence of regulatory components for phosphatase on the control of glutamate-receptor expression. This will be achieved using genetically modified mice strains whose genes for phosphatase-regulatory molecules have been deleted. These animals, along with normal counterparts, will be analyzed in a series of treatments that are known to influence dopamine and glutamate transmission. These studies aim to identify the biochemical processes involved in the action of drugs used in the treatment of TS, and may lead to the design of alternative drug treatments with greater specificity and fewer side effects. Patrick B. Allen, Ph.D., Dept. of Molecular Psychiatry Yale University School of Medicine, New Haven, CT Award: $40,000 In memory of Lodewijk Sankuijl, M.D. who was a key member of the TSA International Consortium for Genetics Tourette Association of America Inc. – Research Grant Award 2003-2004