The overall objective is to characterize the contribution of the intrinsic properties of dopamine neurons to syn- aptic integration. Specifically, we will determine whether modulation of the ether-a-go-go-related gene (ERG) and/or the small conductance calcium-activated (SK) potassium channels alters their response to excitatory synaptic input. Bursts in dopamine neurons are thought to convey the reward prediction and salience signals. Schizophrenia is thought to result from disordered dopaminergic signaling. Antipsychotics attenuate the disor- dered dopaminergic signal, relieving psychosis, and usually partially block the K+ ERG current. The SK current masks background burst firing in dopamine neurons, and we propose the ERG K+ current as an additional, novel intrinsic component of burst firing. The specific hypotheses to be tested in this application are that: 1) the level of spontaneous bursting activity determines the ability of excitatory afferent inputs to trigger time-locked bursting activity and 2) that ERG K+ current in DA neurons provides a safeguard from depolarization block, and by extension ensures that synaptically driven increases in DA cell excitability are encoded and propagated to DA targets. """"""""Depolarization block"""""""", a persistent depolarization in which action potentials are no longer sus- tained due to persistent sodium channel inactivation, is hypothesized to occur when the inward currents that promote bursting activity dominate the outward currents that attenuate it. A decrease in SK current is pre- dicted to facilitate both spontaneous and afferent-driven bursting, and in the presence of reduced ERG K+ cur- rent, to induce depolarization block.
The specific aims are to test the predictions that 1) functional ERG K+ channels are expressed in dopamine neurons, 2) a reduction in SK current facilitates simulated spontaneous and synaptically-driven bursting activity in vitro, and that this bursting activity results to depolarization block unless relieved by the ERG K+ current, and 3) modulation of SK and/or ERG currents in DA neurons alters their ability to produce both spontaneous bursts as well as bursts in response to excitatory synaptic input in vivo. Electrophysiological recordings in rat brain combined with both complex multi-compartmental and simple neural models will be utilized in concert with experiments conducted with selective pharmacological agents to titrate the contribution of these currents to dopaminergic signaling. The modeling component is required to un- derstand the mechanisms underlying the generation of both types of bursting because of the complexity of the oscillatory mechanisms and the interactions between different regions of the dopaminergic neuron that likely function as coupled oscillators. The collective activity of the system is likely to have fundamentally different dy- namics in vivo compared to in vitro because of the interaction of intrinsic and synaptic mechanisms. A better understanding of how the firing pattern of DA neurons is regulated could result in the development of novel therapeutic targets for treating a variety of DA related disorders including Parkinson's disease, schizophrenia, drug and alcohol abuse.

Public Health Relevance

Both experiments and computer modeling will be used to characterize the contributions of the ether-a-go-go-related gene (ERG) and small conductance (SK) potassium channels to the electrical activity of midbrain dopamine neurons. A better understanding of this activity, and specifically of the role of these currents in regulating the firing pattern in these neurons, may lead to improved therapeutics for both Parkinson's and schizophrenia, as well as other disorders involving dopaminergic signaling such as drug abuse.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-L (03))
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State Univ Hsc New Orleans
Schools of Medicine
New Orleans
United States
Zip Code
Canavier, Carmen C; Evans, Rebekah C; Oster, Andrew M et al. (2016) Implications of cellular models of dopamine neurons for disease. J Neurophysiol 116:2815-2830
Yu, Na; Canavier, Carmen C (2015) A Mathematical Model of a Midbrain Dopamine Neuron Identifies Two Slow Variables Likely Responsible for Bursts Evoked by SK Channel Antagonists and Terminated by Depolarization Block. J Math Neurosci 5:5
Yu, Na; Tucker, Kristal R; Levitan, Edwin S et al. (2014) Implications of cellular models of dopamine neurons for schizophrenia. Prog Mol Biol Transl Sci 123:53-82
Qian, Kun; Yu, Na; Tucker, Kristal R et al. (2014) Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons. J Neurophysiol 112:2779-90
Ji, Huifang; Tucker, Kristal R; Putzier, Ilva et al. (2012) Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block. Eur J Neurosci 36:2906-16
Tucker, Kristal R; Huertas, Marco A; Horn, John P et al. (2012) Pacemaker rate and depolarization block in nigral dopamine neurons: a somatic sodium channel balancing act. J Neurosci 32:14519-31
Kuznetsova, Anna Y; Huertas, Marco A; Kuznetsov, Alexey S et al. (2010) Regulation of firing frequency in a computational model of a midbrain dopaminergic neuron. J Comput Neurosci 28:389-403
Canavier, C C; Shepard, P D (2009) Chaotic versus stochastic dynamics: a critical look at the evidence for nonlinear sequence dependent structure in dopamine neurons. J Neural Transm Suppl :121-8
Putzier, Ilva; Kullmann, Paul H M; Horn, John P et al. (2009) Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons. J Neurosci 29:15414-9