Robust Pacemaking in Substantia Nigra Dopaminergic Neurons

<jats:p>Dopaminergic neurons of the substantia nigra pars compacta are autonomous pacemakers. This activity is responsible for the sustained release of dopamine necessary for the proper functioning of target structures, such as the striatum. Somatodendritic L-type Ca<jats:sup>2+</jats:sup>channels have long been viewed as important, if not necessary, for this activity. The studies reported here challenge this viewpoint. Using a combination of optical and electrophysiological approaches in brain slices, it was found that antagonism of L-type Ca<jats:sup>2+</jats:sup>channel effectively stopped dendritic Ca<jats:sup>2+</jats:sup>oscillations but left autonomous pacemaking unchanged. Moreover, damping intracellular Ca<jats:sup>2+</jats:sup>oscillations with exogenous buffer had little effect on pacemaking rate. Although not necessary for pacemaking, L-type channels helped support pacemaking when challenged with cationic channel blockers. Simulations suggested that the insensitivity to antagonism of L-type channels reflected the multichannel nature of the pacemaking process. The robustness of pacemaking underscores its biological importance and provides a framework for understanding how therapeutics targeting L-type Ca<jats:sup>2+</jats:sup>channels might protect dopaminergic neurons in Parkinson's disease without compromising their function.</jats:p>