The application describes a part of the long-term research program of this laboratory on neuroanatomical and neurochemical organization of the ascending output pathways of the basal ganglia (BG) and cerebellum. The proposed studies are focused on the GABAergic mechanisms of the primate motor thalamus and their changes induced by discrete neurotoxic lesions in different BG structures. Since GABA is the neurotransmitter in the nigro- and pallidothalamic pathways changes in thalamic GABAergic mechanisms can be expected in the course of various movement disorders such as Parkinsonism, Huntington's chorea, dystonias, etc. These can be caused by cell loss in the BG structures which in turn results in alteration of the BG output activity. It is incredible that there have been no systematic studies on the effect of BG lesioning on the targets of the BG output pathways in contrast to the large research effort concentrated on the BG nuclei themselves during the past two decades. This considerably impedes the progress in understanding of the BG function in health and disease. It is proposed to study expression of mRNAs for GABA producing enzyme (glutamic acid decarboxylase, GAD) and various GABAA receptor subunits, as well as binding parameters of several GABAA and benzodiazepine receptor ligands in the nigral, pallidal and cerebellar territories of the primate thalamus and their regulation after lesioning of the medial globus pallidus, substantia nigra and subthalamic nucleus at short- (1 week) and long-term (4 months) survival times. The experiments will test the hypothesis that GABAergic transmission at the terminals of the two BG output pathways (from the medial globus pallidus and substantia nigra pars reticularis) are regulated by different molecular mechanisms at both pre- and postsynaptic levels. The best available techniques to be used include: stereotactic neurosurgery based on ventriculography and intracerebral landmarks, in situ hybridization histochemistry with mRNA probes, receptor binding autoradiography, computer assisted image analysis for quantification of histochemical and autoradiographic results, and light microscopic immunocytochemistry. The studies will generate new information regarding the possible role in dyskinetic disorders of GABAergic systems of the nigral, pallidal and cerebellar afferent territories of the primate thalamus which will serve as the baseline data in future analysis of more complex animal models such as MPTP induced Parkinsonism, for example. The studies have also broader significance in that they will provide unique insights into molecular organization and regulation of thalamic GABAergic systems in primates whose neuroanatomical organization has undergone significant evolutionary specialization and is substantially different from that in rodents on which most of neurochemical studies are currently being done.
