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The Journal of Neuroscience, October 22, 2008, 28(43):10905-10917; doi:10.1523/JNEUROSCI.2237-08.2008

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

Zayd M. Khaliq and Bruce P. Bean

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Zayd M. Khaliq, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: zayd_khaliq{at}hms.harvard.edu

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 <1 pA) between –60 and –55 mV. Under voltage clamp, ramps over subthreshold voltages elicited a time- and voltage-dependent outward current that peaked near –55 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 Ba²⁺, 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 >10 mV/s to act as a powerful, supralinear feedback element. This feedback mechanism explains how net ionic current can be constrained to <1–2 pA but reliably inward, thus enabling slow, regular firing.

Key words: I_A; I_K; 4-aminopyridine; spontaneous firing; A-type; dopaminergic neurons; VTA

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Received May 17, 2008; revised Sept. 10, 2008; accepted Sept. 11, 2008.

Correspondence should be addressed to Zayd M. Khaliq, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: zayd_khaliq{at}hms.harvard.edu

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