Dynamic, Nonlinear Feedback Regulation of Slow Pacemaking by A-Type Potassium Current in Ventral Tegmental Area Neurons

Abstract

We analyzed ionic currents that regulate pacemaking in dopaminergic neurons of the mouse ventral tegmental area by comparing voltage trajectories during spontaneous firing with ramp-evoked currents in voltage clamp. Most recordings were made in brain slice, with key experiments repeated using acutely dissociated neurons, which gave identical results. During spontaneous firing, net ionic current flowing between spikes was calculated from the time derivative of voltage multiplied by cell capacitance, signal-averaged over many firing cycles to enhance resolution. Net inward interspike current had a distinctive nonmonotonic shape, reaching a minimum (generally Ͻ1 pA) between Ϫ60 and Ϫ55 mV. Under voltage clamp, ramps over subthreshold voltages elicited a time-and voltage-dependent outward current that peaked near Ϫ55 mV. This current was undetectable with 5 mV/s ramps and increased steeply with depolarization rate over the range (10 -50 mV/s) typical of natural pacemaking. Ramp-evoked subthreshold current was resistant to ␣-dendrotoxin, paxilline, apamin, and tetraethylammonium but sensitive to 4-aminopyridine and 0.5 mM Ba 2ϩ , consistent with A-type potassium current (I A ). Same-cell comparison of currents elicited by various ramp speeds with natural spontaneous depolarization showed how the steep dependence of I A on depolarization rate results in small net inward currents during pacemaking. These results reveal a mechanism in which subthreshold I A is near zero at steady state, but is engaged at depolarization rates Ͼ10 mV/s to act as a powerful, supralinear feedback element. This feedback mechanism explains how net ionic current can be constrained to Ͻ1-2 pA but reliably inward, thus enabling slow, regular firing.

Ion channel degeneracy enables robust and tunable neuronal firing rates

“…This simple fact results from the membrane equation C m dV =dt = −I m , and the small magnitude of the current has been carefully characterized experimentally (31). Maintaining such a small current implies that voltage dependence of the membrane conductance is relatively insensitive to the membrane potential variations occurring between two spikes.…”

Discharge regularity in the turtle posterior crista: comparisons between experiment and theory

“…It is of interest that in other neurons, where SK channels contribute to medium AHPs, blocking these channels reduces but does not eliminate AHPs (Deister et al 2009;Wolfart and Roeper 2002). Rapidly inactivating, outward I A currents can contribute to medium AHPs (Connor and Stevens 1971;Jackson and Bean 2007;Khaliq and Bean 2008) and are present in vestibular afferents (Dhawan et al 2010;Kalluri et al 2010). The latter conductances have the advantage over SK currents in allowing the orderly encoding of information down to zero discharge (Connor 1978;Smith and Goldberg 1986).…”

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Neuronal Firing in the Suprachiasmatic Nucleus and Circadian Rhythms in Locomotor Activity

“…These unique properties, together with variable dendritic expression patterns, allow I A channels to play important roles in modulating the responses to synaptic inputs and to influence synaptic integration and neuronal output properties (Birnbaum et al, 2004;Jerng et al, 2004). In spontaneously active neurons, like those in the SCN, therefore, I A channels would be expected to function to regulate excitability and the initiation of firing by opposing membrane depolarizations, resulting from the closing/ opening of other channels, as well as influence the voltage trajectory during the interspike interval, which will regulate repetitive firing rates (Connor and Stevens, 1971b;Kang et al, 2000;Kim et al, 2005;Yuan et al, 2005;Khaliq and Bean, 2008) Although I A was previously hypothesized to be critical in regulating the transition from the silent night state to the spontaneously active day state (Kim and Dudek, 1993;Bouskila and Dudek, 1995), the results presented here demonstrate that Kv1.4-and Kv4.2-encoded I A channels are instead critical in determining the threshold for firing of SCN neurons during the day and during the night. Other, yet to be identified subthreshold K ϩ channels, therefore, must be involved in determining the transitions between the night and day patterns of electrical activity in the SCN.…”

“…In many neurons, these properties impact repetitive firing rates (Connor and Stevens, 1971b;Kang et al, 2000;Kim et al, 2005;Yuan et al, 2005;Khaliq and Bean, 2008). In some cells, I A channels are active at subthreshold membrane potentials, influencing cell input resistances and excitability Yuan et al, 2005).…”