Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tuberomammillary neurons

A role for persistent, subthreshold, TTX-sensitive sodium current in driving the pacemaking of many central neurons has been proposed, but this has been impossible to test pharmacologically. Using isolated tuberomammillary neurons, we assessed the role of subthreshold sodium current in pacemaking by performing voltage-clamp experiments using a cell's own pacemaking cycle as voltage command. TTX-sensitive sodium current flows throughout the pacemaking cycle, even at voltages as negative as -70 mV, and this current is sufficient to drive spontaneous firing. When sodium channels underlying transient current were driven into slow inactivation by rapid stimulation, persistent current decreased in parallel, suggesting that persistent sodium current originates from subthreshold gating of the same sodium channels that underlie the phasic sodium current. This behavior of sodium channels may endow all neurons with an intrinsic propensity for rhythmic, spontaneous firing.