Dopamine modulation of Ih improves temporal fidelity of spike propagation in an unmyelinated axon.

We studied how conduction delays of action potentials in an unmyelinated axon depended on the history of activity and how this dependence was changed by the neuromodulator dopamine (DA). The pyloric dilator axons of the stomatogastric nervous system in the lobster, Homarus americanus, exhibited substantial activity-dependent hyperpolarization and changes in spike shape during repetitive activation. The conduction delays varied by several milliseconds per centimeter, and, during activation with realistic burst patterns or Poisson-like patterns, changes in delay occurred over multiple timescales. The mean delay increased, whereas the resting membrane potential hyperpolarized with a time constant of several minutes. Concomitantly with the mean delay, the variability of delay also increased. The variability of delay was not a linear or monotonic function of instantaneous spike frequency or spike shape parameters, and the relationship between these parameters changed with the increase in mean delay. Hyperpolarization was counteracted by a hyperpolarization-activated inward current (I(h)), and the magnitude of I(h) critically determined the temporal fidelity of spike propagation. Pharmacological block of I(h) increased the change in delay and the variability of delay, and increasing I(h) by application of DA diminished both. Consequently, the temporal fidelity of pattern propagation was substantially improved in DA. Standard measurements of changes in excitability or delay with paired stimuli or tonic stimulation failed to capture the dynamics of spike conduction. These results indicate that spike conduction can be extremely sensitive to the history of axonal activity and to the presence of neuromodulators, with potentially important consequences for temporal coding.

Dopamine modulates Ih in a motor axon.

We studied the axons of the pyloric dilator neurons in the stomatogastric nervous system of the lobster. The several-centimeters-long portions of these axons in the motor nerves depolarize in response to low concentrations of dopamine (DA) and exhibit peripheral spike initiation in the absence of centrally generated activity. This effect is inhibited by blockers of hyperpolarization-activated inward current (I(h)). We show here that peripheral spike initiation was also elicited by D(1)-type receptor agonists and drugs that increase cAMP. This suggests that DA acts via a D(1)-type receptor mechanism to modulate hyperpolarization-activated cyclic nucleotide-gated channels. We used two-electrode voltage clamp of the axon to directly study the effect of DA on I(h). Surprisingly, DA decreased the maximal conductance. However, because of a shift of the activation curve to more depolarized potentials, and a change in the slope, conductance was increased at biologically relevant membrane potentials. These changes were solely caused by modulation of I(h), as DA had no discernible effect when I(h) was blocked. In addition, they were not induced by repeated activation and could be mimicked by application of drugs that increase cAMP concentration. DA modulation of I(h) persisted in the presence of a protein kinase A inhibitor and is therefore potentially mediated by a phosphorylation-independent direct effect of cAMP on the ion channel. A computer model of the axon showed that the changes in maximal conductance and voltage dependence were not qualitatively affected by space-clamp problems.

Complex intrinsic membrane properties and dopamine shape spiking activity in a motor axon.

We studied the peripheral motor axons of the two pyloric dilator (PD) neurons of the stomatogastric ganglion in the lobster, Homarus americanus. Intracellular recordings from the motor nerve showed both fast and slow voltage- and activity-dependent dynamics. During rhythmic bursts, the PD axons displayed changes in spike amplitude and duration. Pharmacological experiments and the voltage dependence of these phenomena suggest that inactivation of sodium and A-type potassium channels are responsible. In addition, the "resting" membrane potential was dependent on ongoing spike or burst activity, with more hyperpolarized values when activity was strong. Nerve stimulations, pharmacological block and current clamp experiments suggest that this is due to a functional antagonism between a slow after-hyperpolarization (sAHP) and inward rectification through hyperpolarization-activated current (IH). Dopamine application resulted in modest depolarization and "ectopic" peripheral spike initiation in the absence of centrally generated activity. This effect was blocked by CsCl and ZD7288, consistent with a role of IH. High frequency nerve stimulation inhibited peripheral spike initiation for several seconds, presumably due to the sAHP. Both during normal bursting activity and antidromic nerve stimulation, the conduction delay over the length of the peripheral nerve changed in a complex manner. This suggests that axonal membrane dynamics can have a substantial effect on the temporal fidelity of spike patterns propagated from a spike initiation site to a synaptic target, and that neuromodulators can influence the extent to which spike patterns are modified.