AMINO ACID RECEPTORS AND BASAL GANGLIA FUNCTION

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The basal ganglia play a major role in the control of normal movement and coordination. Lesions of the basal ganglia result in movement disorders ranging from severe akinesia, rigidity and tremor to dystonia, chorea and ballismus. The symptomatology in any particular individual or disease process depends on the distinct subgroups of neurons affected. The neurochemical and functional anatomy of the basal ganglia are now being worked out in detail. The amino acid neurotransmitters appear to mediate neurotransmission at a majority of basal ganglia synapses. The inhibitory amino acid, GABA, is the neurotransmitter for the vast majority of striatal, pallidal and substantia nigra neurons. Excitatory amino acids, (EAA) such as glutamate serve as the neurotransmitters for cortical and thalamic efferents to striatum, subthalamic nucleus and substantia nigra neurons. The subtypes of GABAA and EAA receptors have unique pharmacologies and signal transduction properties. Furthermore, the genes for many of these receptor subtypes have been cloned. Circumstantial evidence suggests that the striatal neurons most vulnerable in Huntington's disease express more NMDA and metabotropic EAA receptors than other striatal neurons. This hypothesis will be tested using double-label in situ hybridization of oligonucleotide probes for these receptors and immunohistochemistry of antibodies directed against the receptor proteins. In previous studies we have found that the different subtypes of GABAA and EAA receptors regulate specifically in response to striatal, cortical, nigral and subthalamic lesions. This work will be extended to investigate the hypothesis that the specific genes for GABAA and non-NMDA receptor subtypes regulate differentially after selective lesions of basal ganglia subnuclei. We will combine autoradiography of ligand binding with in situ hybridization of oligonucleotide probes for GABAA, AMPA, and metabotropic receptor subunits. We anticipate that those receptors that regulate after lesions may not be those that are predominantly expressed under normal conditions. Elucidation of the details of receptor regulation in these animal models of Huntington's disease, Parkinson's disease, dystonia, and hemiballismus will allow us to devise more effective pharmacotherapies for these illnesses using drugs selective for the various receptor subtypes. Such studies will also add to the understanding of basal ganglia circuitry in health and disease.