A concerted action of L- and T-type Ca2+ channels regulates locus coeruleus pacemaking

Dysfunction of noradrenergic locus coeruleus (LC) neurons is involved in psychiatric and neurodegenerative diseases and is an early hallmark of Parkinson's disease (PD). The analysis of ion channels underlying the autonomous electrical activity of LC neurons, which is ultimately coupled to cell survival signaling pathways, can lead to a better understanding of the vulnerability of these neurons. In LC neurons somatodendritic Ca2+ oscillations, mediated by L-type Ca2+ channels, accompany spontaneous spiking and are linked to mitochondrial oxidant stress. However, the expression and functional implication of low-threshold activated T-type Ca2+ channels in LC neurons were not yet studied. To this end we performed RT-PCR expression analysis in LC neurons. In addition, we utilized slice patch clamp recordings of in vitro brainstem slices in combination with L-type and T-type Ca2+ channel blockers. We found the expression of a distinct set of L-type and T-type Ca2+ channel subtypes mediating a pronounced low-threshold activated Ca2+ current component. Analyzing spike trains, we revealed that neither L-type Ca2+ channel nor T-type Ca2+ channel blockade alone leads to a change in firing properties. In contrast, a combined application of antagonists significantly decreased the afterhyperpolarization amplitude, resulting in an increased firing frequency. Hence, we report the functional expression of T-type Ca2+ channels in LC neurons and demonstrate their role in increasing the robustness of LC pacemaking by working in concert with Cav1 channels. (C) 2015 Elsevier Inc. All rights reserved.