Physiology of Muscarinic Synapses in Sympathetic Ganglia

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DESCRIPTION (provided by applicant): This project will determine how interactions between nicotinic and muscarinic synapses regulate information processing in paravertebral sympathetic ganglia. The goal is to understand molecular and cellular mechanisms of synaptic transmission in terms of their essential role in cardiovascular regulation and other forms of autonomic behavior. Towards this end, a mathematical theory of ganglionic integration has been recently developed. It predicts that sympathetic ganglia function as variable synaptic amplifiers of neural activity. In this framework, nicotinic synapses and presynaptic activity are the basic determinants of synaptic gain, while muscarinic mechanisms and other forms of short-term synaptic plasticity serve to regulate synaptic gain. To date, the most direct evidence for the theory has come from experimental studies of secretomotor sympathetic B neurons in the bullfrog. The proposed experiments will generalize the synaptic gain hypothesis by extending experimental studies to vasomotor sympathetic C neurons in the bullfrog and to homologous cell types in the rat and mouse. Taking a comparative approach will exploit the advantages of each system and distinguish general principles from other forms of variability associated with evolutionary specialization. The proposed research will combine methods of cellular electrophysiology, computational modeling, and anatomy. There are five specific aims. Aim 1 will test whether a common rule can describe nicotinic convergence in bullfrog C neurons and in the mammalian superior cervical sympathetic ganglion. Aim 2 will establish how oscillations in preganglionic activity regulate synaptic gain. Aim 3 will determine whether phenotypic differences in postsynaptic excitability influence synaptic gain. Aim 4 will resolve how multiple components of postsynaptic muscarinic excitation regulate synaptic gain. Aim 5 will analyze how the dynamics of transmitter release influence synaptic gain. The project's long-term goal is to develop molecular hypotheses of ganglionic integration that can be tested by observing sympathetic behavior in hypertensive strains of rats and in genetically altered mice. The project is important because it will elucidate fundamental mechanisms of neural information processing. It will also have broad implications for understanding autonomic behaviors whose disruption by disease creates major public health problems.