Glutamate is the principal excitatory neurotransmitter in the brain and has an important role in the regulation of movement. N-methyl-D-aspartate (NMDA) glutamate receptors are of particular interest because they are involved in long-term processes such as neural adaptation and memory. Drugs acting at NMDA receptors have important therapeutic potential in human Parkinson's disease. In particular, recent work has suggested that changes in NMDA receptor properties may be responsible for the development of the motor complications of levodopa therapy, such as wearing off and dyskinesias. Such motor complications occur in the majority of patients with Parkinson's disease and are frequently the principal cause of disability. NMDA receptors are assembled from proteins from two gene families, and receptors with different composition have distinct properties. The functions of the receptors are further regulated by differential trafficking and phosphorylation. Our investigations have revealed that neurons which serve different functions in the circuitry of the basal ganglia express different types of NMDA receptor subunits. In models of Parkinsonism, striatal NMDA receptors are modified. The most significant changes are not alterations in the level of gene expression, but rather are changes in the assembly, phosphorylation, and synaptic localization of the protein subunits. In this project, we will employ a variety of techniques to establish the nature and mechanisms of the modifications of basal ganglia NMDA receptors produced by chronic dopamine depletion and dopamine replacement therapy. The long term goal of this work is to gain insight into the cause of wearing off and dyskinesias in Parkinson's disease, and develop better treatments for this common and disabling neurological disorder.
NIH ExPorter
NIH ExPorter