Physiology of Muscarinic Synapses in Sympathetic Ganglia

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Sympathetic and parasympathetic ganglia provide the final common pathway for ail central motor control of smooth muscle, cardiac muscle and glands in tissues that mediate autonomic behavior. The long-term goals of this project are to determine how the neural architecture of autonomic ganglia enables them to transform spike trains, to elucidate how molecular and cellular mechanisms of synaptic plasticity shape this process, and to define the principles of ganglionic integration that contribute to behavior. The proposed work will focus upon modulatory muscarinic synapses in sympathetic ganglia, with emphasis on the subset of neurons that control cardiovascular function. The project will employ cellular neurophysiology, computational simulations, and neuroanatomy methods in 2 model systems - bullfrog sympathetic ganglia and the rat superior cervical sympathetic ganglion. Many of the physiological experiments will use the dynamic clamp method to implement virtual nicotinic synapses on living neurons and then determine how they interact with metabotropic neuromodulatory mechanisms. The analysis is predicated upon a working hypothesis that paravertebral sympathetic ganglia behave as variable synaptic amplifiers of activity whose gain is regulated by the strength and convergence of nicotinic synapses and by the expression of neuromodulatory mechanisms that serve to adjust the strength of nicotinic synapses. The specific aims are: 1) To contrast activity-dependent muscarinic gain modulation in 3 different sympathetic cell types. 2) To measure the contributions of quantal noise and presynaptic plasticity to synaptic gain. 3) To analyze the regulation of ganglionic integration by cardiac rhythms. 4) To test the hypothesis that metabotropic signaling through muscarinic, alpha-adrenergic and angiotensin II receptors provides a basis for phenotypic specialization of ganglionic integration in the rat SCG. Concepts developed through this research will contribute to fundamental understanding of normal autonomic behavior and human pathophysiology, especially to changes associated with syncope, hypertension and heart failure. [unreadable] [unreadable]