POSTSYNAPTIC FACTORS AFFECTING SYNAPTIC EFFICACY

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Our long-term objective are to determine the principles of operation of central synapses and of neuronal circuits. We are particularly interested in elucidating properties of the postsynaptic membranes which influence the efficacy and time course of synaptic transmission and which also might provide substrate 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 structrul parameters. The latter include the receptor or biding site densities, the sub-synaptic location of the receptors, the dimensions of the synaptic contact zone, and the localizations of imputes from the same or different sources., Another important factor is the presence or avsece of transmitter inactivation mechanism which influence the extent to which adjacent synapses interact The proposed research is designed to study central inhibitory (glycinergic) and excitatory (possibly glutamateric): synapses on an identified vertebrate neuron, the ogodfish Mauthner cell, and to develop a computer model of the quanta responses. Much of the work is based on the notion that non-liner interactions between adjacent synapses can be due to lateral diffusion of transmitter from one contact to the next, with, in some cases, allosteric modulation of receptor properties. Specially aims include studying 1) synergistic interactions between adjacent glycinetregic synapses, 2) allosteric regulation of glycinergic and glutamamterigc synaptic responses by GABA and glycine, respectively, 3) effects of blocking glycine uptake on inhibitory responses, 4) modulation of glycinergic responses by postsynaptic injections of cAMP 5) properties and modulation of apparently silent connected , and 6) the glutamate receptor a at Mauthner cell excitatory synapses. Also, a computer model of quanta responses will be modified to incorporate effects of co-activation or adjacent synapses. Most experiments will involve voltage clamp measurements of synaptic currents, and transmitter iontophoresis will also be used. These studies should provide a foundation for understanding emergent properties of neuronal networks and their plasticity and for suggesting new mechanisms for exogenous modulation of synaptic transmission in disease states.