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.