A model for pleiotropic muscarinic potentiation of fast synaptic transmission

The predominant form Of muscarinic excitation in the forebrain and in sympa thetic ganglia arises from mi receptors coupled to the G(q/11) signal trans duction pathway. Functional components of this system have been most comple tely mapped in frog sympathetic B neurons. Presynaptic stimulation of the B neuron produces a dual-component muscarinic excitatory postsynaptic potent ial (EPSP) mediated by suppression of voltage-dependent M-type K+ channels and activation of a voltage-insensitive cation current. Evidence from mamma lian systems suggests that the cation current is mediated by cyclic GMP-gat ed channels. This paper describes the use of a computational model to analy ze the consequences of pleiotropic muscarinic signaling for synaptic integr ation. The results show that the resting potential of B neurons is a logari thmic function of the leak conductance over a broad range of experimentally observable conditions. Small increases (<4 nS) in the muscarinically regul ated cation conductance produce potent excitatory effects. Damage introduce d by intracellular recording can mask the excitatory effect of the muscarin ic leak current. Synaptic activation of the leak conductance combines syner gistically with suppression of the M-conductance (40 --> 20 nS) to strength en fast nicotinic transmission. Overall, this effect can more than double s ynaptic strength, as measured by the ability of a fast nicotinic EPSP to tr igger an action potential. Pleiotropic muscarinic excitation can also doubl e 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 m uscarinic actions. The results are discussed in terms of their implications for synaptic integration in sympathetic ganglia and other circuits.