Glutamate is the principal excitatory neurotransmitter of the brain and plays an important role in the neural circuits of the basal ganglia which are responsible for the control of movement. Of the several classes of glutamate receptors, NMDA receptors are of particular interest because they are central to the processes regulating movement, and may be involved in long-term adaptive processes such as motor learning, and are currently the target of efforts to develop new drugs for the treatment of human disorders of movement such as Parkinson's disease. The genes encoding the subunits of the NMDA receptor have been cloned; a total of 12 distinct proteins from two gene families have been identified. It is believed that NMDA receptors are formed by the combination of five of the subunits, and that the physiological and pharmacological properties of the resultant NMDA channels are regulated by the types of subunits present. Previous investigations have shown that NMDA receptors are abundant in the structures of the basal ganglia, but the types of subunits in each structure are different. These findings suggest that although NMDA receptors are present throughout the brain, the receptors in different components of the basal ganglia circuitry are likely to have different subunit compositions and different properties. The applicant plans to undertake a series of investigations with two primary goals: 1) to investigate the regional, cellular, and intracellular expression of NMDA receptor subunit mRNAs and proteins in the basal ganglia, and form hypotheses regarding the function of these subunits; 2) to employ synthetic oligonucleotides (""""""""antisense oligonucleotides"""""""") to inhibit the synthesis of specific NMDA receptor subunits to study the physiological roles of these subunits in the regulation of movement. It is anticipated that the results of these investigations will provide important information on the function of NMDA receptor subunits and complexes in the regulation of motor function controlled by the basal ganglia, and provide a basis for rational design of therapeutic agents for human disorders of movement.
