The long-term goal of this project is to understand the consequences of synaptic of cotransmission for information processing in sympathetic ganglia. Isolated preparations of bullfrog paravertebral sympathetic ganglia will be used for electrophysiological studies of muscarinic and peptidergic mechanisms that are co-activated by stimulation of preganglionic nerves and serve to modulate nicotinic transmission. The bullfrog system has been chosen because of its relatively simple and well-defined organization. Ganglion cells display 2 major phenotypes: B neurons innervate cutaneous glands and C neurons innervate arteries. Recent experiments indicate that interactions between subthreshold nicotinic EPSPs and modulatory synaptic events play a central role in ganglionic integration. These interactions have been previously overlooked because, under the conditions used in most cellular studies, they are overshadowed by strong suprathreshold nicotinic synapses. The proposed experiments have been designed to analyze subthreshold EPSPs in a manner that is relevant to normal in vivo patterns of asynchronous preganglionic activity.
The Aims of the proposal are focused on 3 specific questions: 1) What are the integrative consequences of synaptic convergence in ganglia?, 2) What are the integrative consequences of presynaptic inhibition in ganglia?. 3) What is the mechanism for modulation of muscarinic and peptidergic cotransmission by the drug nicotine?.
A fourth aim i s to develop a mathematical model of ganglionic integration and fit it to the experimental data collected for aims 1 and 2. The goal is to explore dynamic properties of cotransmission that can not be directly observed through experiment and to develop testable predictions of postganglionic firing, in vivo. This project will provide fundamental new information about cellular mechanisms of synaptic cotransmission and a formalism for generalizing the results form a simple model system to mammalian systems. The nicotine experiments are important because they may define the primary cellular mechanism mediating the peripheral autonomic effects of smoking.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021065-12
Application #
2431136
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Baughman, Robert W
Project Start
1984-07-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
12
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Springer, Mitchell G; Kullmann, Paul H M; Horn, John P (2015) Virtual leak channels modulate firing dynamics and synaptic integration in rat sympathetic neurons: implications for ganglionic transmission in vivo. J Physiol 593:803-23
Kullmann, Paul H M; Horn, John P (2010) Vasomotor sympathetic neurons are more excitable than secretomotor sympathetic neurons in bullfrog paravertebral ganglia. Auton Neurosci 155:19-24
Rimmer, Katrina; Horn, John P (2010) Weak and straddling secondary nicotinic synapses can drive firing in rat sympathetic neurons and thereby contribute to ganglionic amplification. Front Neurol 1:130
Kullmann, Paul H M; Horn, John P (2010) Homeostatic regulation of M-current modulates synaptic integration in secretomotor, but not vasomotor, sympathetic neurons in the bullfrog. J Physiol 588:923-38
Li, Chen; Horn, John P (2008) Differential Inhibition of Ca2+ channels by alpha2-adrenoceptors in three functional subclasses of rat sympathetic neurons. J Neurophysiol 100:3055-63
Horn, J P; Kullmann, P H M (2007) Dynamic Clamp Analysis of Synaptic Integration in Sympathetic Ganglia. Neirofiziologiia 39:423-429
Headley, Drew B; Suhan, Nadine M; Horn, John P (2007) Different subcellular distributions of the vesicular monoamine transporter, VMAT2, in subclasses of sympathetic neurons. Brain Res 1129:156-60
Li, Chen; Horn, John P (2006) Physiological classification of sympathetic neurons in the rat superior cervical ganglion. J Neurophysiol 95:187-95
Kullmann, Paul H M; Horn, John P (2006) Excitatory muscarinic modulation strengthens virtual nicotinic synapses on sympathetic neurons and thereby enhances synaptic gain. J Neurophysiol 96:3104-13
Headley, Drew B; Suhan, Nadine M; Horn, John P (2005) Rostro-caudal variations in neuronal size reflect the topography of cellular phenotypes in the rat superior cervical sympathetic ganglion. Brain Res 1057:98-104

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