Canavier, Carmen C

Huertas, Marco A

Ji, Huifang

Levitan, Edwin

Shepard, Paul D

Tucker, Kristal

D-Scholarship@Pitt

POSTER PRESENTATION Open AccessThe role of ERG current in pacemaking andbursting in dopamine neuronsMarco A Huertas1*, Huifang Ji3, Kristal Tucker2, Edwin Levitan2, Paul D Shepard3, Carmen C Canavier1From Twentieth Annual Computational Neuroscience Meeting: CNS*2011Stockholm, Sweden. 23-28 July 2011Dopamine (DA) neurons exhibit regular, pacemakingfiring in the range of 1-8 Hz in in vitro preparationsand are observed to produce bursts of action potentialsat much higher frequencies in in vivo studies. Themodel used in the present study expands on our pre-viously published compartmental DA neuron model [1]and incorporates improved descriptions for the L-typeCa2+[2], Na [3] and ERG currents [4]. The approach isto calibrate the model using various types of dataacquired in vitro in order to confidently model andexplain the effects of drug application in vivo. One vali-dation of the new model dynamics is its ability, withoutfurther calibration, to simulate a novel type of burstingobserved in vitro when the SK current is blocked. Inthis type of bursting, the silent phase of the burst is adepolarized plateau, and the active phase consists ofspiking with increasing frequency leading into a briefbut intense burst of spike terminating in depolarizationblock [5].Here we focus on the role of the Ether-a-go-go-relatedgene (ERG) K+ current. The ERG current has the unu-sual characteristic that channels inactivate faster thanthey activate, and upon recovery from inactivation theypass through the open state before they enter the closedstate. Our model predicts that enough of these channelsremain in the open state during pacemaking to slow thefrequency of pacemaking, even though there is not suffi-cient activation of these channels at hyperpolarizedpotentials to affect the input resistance. Indeed, we haveshown that blocking the ERG current in a slice prepara-tion with either E4031 or the toxin rBeKm-1 dose-dependently increases the spontaneous firing rate by50% without significantly altering the membraneresistance. The model includes background noise levelsand can faithfully reproduce the increased precision ofDA cell firing when the ERG current is blocked.Furthermore, we have conducted dynamic clamp experi-ments in which bursts are evoked by injecting a squarepulse of virtual NMDA conductance in the soma. Block-ing the ERG current shortens the burst because thespike frequency under these conditions is also increased.As a result, the burst is terminated as the cell entersinto depolarization block sooner than in the absence ofthis current. In contrast, local application of E-4031 viapassive diffusion from an extracellular recording elec-trode in vivo caused a decline in the number of spikedoublets observed and a concomitant increase in burstscomprised of 3 to 5 spikes per burst. The difference inthe effect of ERG block under these two conditions islikely due to the difference between evoking a singleburst using the dynamic clamp, and the burst dynamicsin vivo that are regulated by the interactions betweenthe L-type Ca2+, NMDA, SK current and ERG currents.The model also predicts a role for the ERG current intermination of depolarized plateaus [6] that follow spikebursts.AcknowledgementsThis work is supported by NIH grant NS 61097 to Carmen C Canavier.Author details1Neuroscience Center of Excellence, LSU Health Sciences Center, NewOrleans, LA 70112, USA. 2Department of Pharmacology and ChemicalBiology, University of Pittsburgh, Pittsburgh, PA 15261, USA. 3MarylandPsychiatric Research Center, University of Maryland School of Medicine,Baltimore, MD 21201, USA.Published: 18 July 2011References1. Kuznetsova AY, Huertas MA, Kuznetsov AS, Paladini CA, Canavier C:Regulation of firing frequency in a computational model of a midbraindopaminergic neuron. J Comput Neurosci 2010, 28(3):389-403.* Correspondence: mhuer1@lsuhsc.edu1Neuroscience Center of Excellence, LSU Health Sciences Center, NewOrleans, LA 70112, USAFull list of author information is available at the end of the articleHuertas et al. BMC Neuroscience 2011, 12(Suppl 1):P27http://www.biomedcentral.com/1471-2202/12/S1/P27© 2011 Huertas et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.2. Putzier I, Kullmann PH, Horn JP, Levitan ES: Cav1.3 channel voltagedependence, not Ca2+ selectivity, drives pacemaker activity andamplifies bursts in nigral dopamine neurons. J Neurosci 2009,29(49):15414-15419.3. Seutin V, Engel D: Differences in Na+ conductance density and Na+channel functional properties between dopamine and GABA neurons ofthe rat substantia nigra. J Neurophysiol 2010, 103(6):3099-3114.4. Ficker E, Jarolimek W, Brown AM: Molecular determinants of inactivationand dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels. Mol Pharmacol 2001, 60(6):1343-1348.5. Ping HX, Shepard PD: Apamin-sensitive Ca(2+)-activated K+ channelsregulate pacemaker activity in nigral dopamine neurons. Neuroreport1996, 7(3):809-814.6. Canavier CC, Oprisan SA, Callaway JC, Ji H, Shepard PD: Computationalmodel predicts a role for ERG current in repolarizing plateau potentialsin dopamine neurons: implications for modulation of neuronal activity. JNeurophysiol 2007, 98(5):3006-3022.doi:10.1186/1471-2202-12-S1-P27Cite this article as: Huertas et al.: The role of ERG current in pacemakingand bursting in dopamine neurons. BMC Neuroscience 2011 12(Suppl 1):P27.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitHuertas et al. BMC Neuroscience 2011, 12(Suppl 1):P27http://www.biomedcentral.com/1471-2202/12/S1/P27Page 2 of 2

The role of ERG current in pacemaking and bursting in dopamine neurons

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The role of ERG current in pacemaking and bursting in dopamine neurons

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