Pacemaker rate and depolarization block in nigral dopamine neurons: A somatic sodium channel balancing act

Midbrain dopamine (DA) neurons are slow intrinsic pacemakers that undergo depolarization (DP) block upon moderate stimulation. Understanding DP block is important because it has been correlated with the clinical efficacy of chronic antipsychotic drug treatment. Here we describe how voltage-gated sodium (Na_V) channels regulate DP block and pacemaker activity in DA neurons of the substantia nigra using rat brain slices. The distribution, density, and gating of Na_V currents were manipulated by blocking native channels with tetrodotoxin and by creating virtual channels and anti-channels with dynamic clamp. Although action potentials initiate in the axon initial segment and Na_V channels are distributed in multiple dendrites, selective reduction of Na_V channel activity in the soma was sufficient to decrease pacemaker frequency and increase susceptibility to DP block. Conversely, increasing somatic Na_V current density raised pacemaker frequency and lowered susceptibility to DP block. Finally, when Na_V currents were restricted to the soma, pacemaker activity occurred at abnormally high rates due to excessive local subthreshold Na_V current. Together with computational simulations, these data show that both the slow pacemaker rate and the sensitivity to DP block that characterizes DA neurons result from the low density of somatic Na_V channels. More generally, we conclude that the somatodendritic distribution of NaV channels is a major determinant of repetitive spiking frequency.