An experiment-based robust model for slow pacemaking

Slow pacemaking refers to the ability of excitable cells to spontaneously generate
action potentials at a stable low frequency (< 10 Hz). For such pacemaking, the
depolarization speed between action potentials is slow (10-30 mV/). In midbrain
dopaminergic (DA) neurons, the pacemaking current has been calculated to be in
the order of 1 to 5 pA. This is close to the current flowing through one Nav or Cav
channel. Given the stochastic nature of ion channel opening, we hypothesized that
the recruitment of many small conductances (in the range of fS) would be better
suited to sustain a stable, slow pacemaking. In a previous study, we isolated a small
current in DA neurons using the gating-pore blocker 1-(2,4-xylyl)guanidinium (XG).
While we could not determine its nature, this XG-sensitive current has properties
that are similar to those of a pacemaker current. We therefore modeled this
conductance and implemented it in a simplified DA conductance-based model to
test its effectiveness to generate pacemaking. In the literature, most pacemaking
conductance-based models use non-physiological values of parameters to
generate slow spiking activity. Adding this newly measured conductance enabled
robust pacemaking activity with physiological parameters using only Na and KDR
conductances. Adding other conductances, such as Cav ones, did not disrupt the
robustness of the pacemaking. While modelling pacemaking usually requires a
tuning of the conductance parameters, our model is the first to precisely match
pacemaking activity studied ex vivo.