RT Journal Article
SR Electronic
T1 Pacemaker Rate and Depolarization Block in Nigral Dopamine Neurons: A Somatic Sodium Channel Balancing Act
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14519
OP 14531
DO 10.1523/JNEUROSCI.1251-12.2012
VO 32
IS 42
A1 Kristal R. Tucker
A1 Marco A. Huertas
A1 John P. Horn
A1 Carmen C. Canavier
A1 Edwin S. Levitan
YR 2012
UL http://www.jneurosci.org/content/32/42/14519.abstract
AB 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 (NaV) channels regulate DP block and pacemaker activity in DA neurons of the substantia nigra using rat brain slices. The distribution, density, and gating of NaV 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 NaV channels are distributed in multiple dendrites, selective reduction of NaV channel activity in the soma was sufficient to decrease pacemaker frequency and increase susceptibility to DP block. Conversely, increasing somatic NaV current density raised pacemaker frequency and lowered susceptibility to DP block. Finally, when NaV currents were restricted to the soma, pacemaker activity occurred at abnormally high rates due to excessive local subthreshold NaV 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 NaV channels. More generally, we conclude that the somatodendritic distribution of NaV channels is a major determinant of repetitive spiking frequency.