Our long-term objectives are to determine the principles of operation of central synapses, particularly the properties of postsynaptic membranes which influence the efficacy and time course of synaptic transmission and which also might provide substrates for neuronal plasticity. Significant postsynaptic properties include the parameters of transmitter-receptor interactions, which should provide a basis for development of rational drug therapies, and structural parameters. The latter include receptor or binding site densities at synaptic and extra-synaptic loci and the dimensions of the synaptic cleft, the postsynaptic receptor matrix, and the synaptic contact zone. Many of these structural parameters are altered in pathological conditions, such as in myasthenia gravis, and as a result of experience or neuronal responses to injury. Nevertheless, there is no comprehensive model which allows us to interpret the consequences of these structural modifications for neuronal function. The proposed research is designed to study the organization of a central glycinergic junction, by studying the inhibitory responses of an identified vertebrate central neuron, the goldfish Mauthner cell, and to develop a computer model of the responses.
Specific aims i nclude 1) an electrophysiological analysis of the properties of the glycine activated channels and of quantal inhibitory responses in vivo, and 2) a study of whether the effects mediated by evoked glycine release are limited by diffusion or uptake/inactivation mechanisms. In addition, preliminary data utilizing strychnine antagonism of glycine mediated responses has led to the hypothesis that adjacent presynaptic terminals of the same or different afferents may have overlapping postsynaptic domains. A third (3) specific aim is to test this hypothesis by studying, with voltage clamp techniques, the interactions of postsynaptic responses to activation of different individual neurons or of clusters of presynaptic neurons. The electrophysiological experiments will involve voltage clamp of the Mauthner cell, in vivo. finally, a fourth aim is to use the experimental data to test and strengthen the computer model of quantal responses, to provide a concrete foundation for understanding the functional roles exerted by different structural parameters and the effects of altering these parameters.
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