Chemical communication between neurons, and between neurons and glia is a basic mechanism essential to normal function within the nervous system. In many neural circuits, the neurochemical signal is transduced into a meaningful postsynaptic message by intracellular second messengers within the target cell. Changes in the process of information transfer at synapses produces a variety of disorders. The deterioration of somatic neurochemical pathways associated with the caudate nucleus of the basal ganglia, contributes significantly to the etiologies of Huntington's disease, Parkinsonism, and age-related dyskinesias. Loss of normal activity at a synapse can be due to alterations in: 1) neurotransmitter release, 2) neurotransmitter receptor binding, 3) second messenger production, or 4) postsynaptic translation of this signal. The present research program is directed at the study of the second messenger compounds, cyclic AMP and cyclic GMP, in the process of information transduction within the caudate nucleus. My approach is to employ morphological techniques in intact, highly organized tissues, to identify specific neurotransmitter receptor molecules, located on identified efferent striatal neurons, with radiolabeled receptor ligands. In combination with this process, will be the simultaneous indentification of cyclic AMP- and/or cyclic GMP-containing perikarya. I plan to establish the preferential relationships between known neurotransmitter receptor occupancy and second messenger cyclic nucleotide content within the postsynaptic target cell. I will also employ two model systems to further expand the study of the cyclic nucleotide mediation of synaptic activity in specified cells. These model systems are in vivo rat caudate tissue slice, and in vitro dissociated cultures from the superior cervical ganglion. These systems have been very well-characterized using a number of experimental approaches. The ultimate establishement of transmitter-sensitive cyclic nucleotide second messengers in proximity to the active region of the synapse will be demonstrated with the use of energy dispersive X-ray microanalysis of scanning transmission electron microscopic samples of the two model systems. Quantitation of cyclic nucleotide production and hydrolysis can be determined through analysis of heavy metal labels on specific neurotransmitter compounds, at receptors sites, or on second messenger chemicals. This will unequivocally show the relationship of the second messenger cyclic nucleotides to defined synaptic terminals that have been activated and released a primary transmitter message onto their postsynaptic target cells.
