The Journal of Neurophysiology Vol. 83 No. 4 April 2000, pp. 1912-1923
Copyright ©2000 by the American Physiological Society

A Model for Pleiotropic Muscarinic Potentiation of Fast Synaptic Transmission

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Schobesberger, Hermann, Diek W. Wheeler, and John P. Horn. A Model for Pleiotropic Muscarinic Potentiation of Fast Synaptic Transmission. J. Neurophysiol. 83: 1912-1923, 2000. The predominant form of muscarinic excitation in the forebrain and in sympathetic ganglia arises from m1 receptors coupled to the G_q/11 signal transduction pathway. Functional components of this system have been most completely mapped in frog sympathetic B neurons. Presynaptic stimulation of the B neuron produces a dual-component muscarinic excitatory postsynaptic potential (EPSP) mediated by suppression of voltage-dependent M-type K⁺ channels and activation of a voltage-insensitive cation current. Evidence from mammalian systems suggests that the cation current is mediated by cyclic GMP-gated channels. This paper describes the use of a computational model to analyze the consequences of pleiotropic muscarinic signaling for synaptic integration. The results show that the resting potential of B neurons is a logarithmic function of the leak conductance over a broad range of experimentally observable conditions. Small increases (<4 nS) in the muscarinically regulated cation conductance produce potent excitatory effects. Damage introduced by intracellular recording can mask the excitatory effect of the muscarinic leak current. Synaptic activation of the leak conductance combines synergistically with suppression of the M-conductance (40  20 nS) to strengthen fast nicotinic transmission. Overall, this effect can more than double synaptic strength, as measured by the ability of a fast nicotinic EPSP to trigger an action potential. Pleiotropic muscarinic excitation can also double the temporal window of summation between subthreshold nicotinic EPSPs and thereby promote firing. Activation of a chloride leak or suppression of a K⁺ leak can substitute for the cation conductance in producing excitatory muscarinic actions. The results are discussed in terms of their implications for synaptic integration in sympathetic ganglia and other circuits.