The objective of the proposed research is to characterize the anatomy of two synaptic circuits in the forebrain: glutamatergic corticostriatal connections and GABAergic striatonigral connections. The principal actions of the synapses of these connections are excitatory and inhibitory, respectively. Together these connections represent an important route of information processing through the mammalian basal ganglia. They are necessary for the normal development and mature physiological operation of the forebrain. Their pathological destruction is associated with severe human neurological diseases including congenital diplegia, Huntington's disease, and stroke. The mature arrangement, developmental organization and response to brain injury of corticostriatal and striatonigral neurons will be determined in cats, a well-characterized animal model of forebrain anatomy and physiology. The experiments will incorporate combinations of connectivity, transmitter and somatodendritic markers to identify the fine structure and biochemistry of the circuits. The research will be focused on the final events in the formation of the connections: the morphogenesis of pre- and post-synaptic specializations and the presynaptic localization of amino acid transmitters. Three hypotheses will be tested: 1) that the establishment of corticostriatal connections triggers the expression of transmitters and the synaptogenesis of striatonigral connections, 2) that the formation of synaptic inputs directs the final stages of dendritic morphogenesis in neostriatal and nigral neurons and 3) that striatonigral connections respond differently to the loss of synaptic inputs induced by failure-to-form, by removal at an immature stage and by removal at a mature stage. The failure or misdirections of these cell-cell interactions can play a critical role in the pathogenesis of human mental retardation. The remodeling of these connections after early and late damage is also of great importance for the anatomical pathology and possible treatment of developmental disabilities and late- appearing genetic disorders.
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