TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

Ki Bum Um,Yoon Je Lee,So Woon Kim,Hyun Jin Kim,Suyun Hahn,Lutz Birnbaumer,Myoung Kyu Park

doi:10.7554/elife.70920

Abstract

Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold slow depolarization underlies autonomous pacemaking and determines its rate. However, the ion channels that determine slow depolarization are unknown. Here we show that TRPC3 and NALCN channels together form sustained inward currents responsible for the slow depolarization of nigral DA neurons. Specific TRPC3 channel blockade completely blocked DA neuron pacemaking, but the pacemaking activity in TRPC3 knock-out (KO) mice was perfectly normal, suggesting the presence of compensating ion channels. Blocking NALCN channels abolished pacemaking in both TRPC3 KO and wild-type mice. The NALCN current and mRNA and protein expression are increased in TRPC3 KO mice, indicating that NALCN compensates for TRPC3 currents. In normal conditions, TRPC3 and NALCN contribute equally to slow depolarization. Therefore, we conclude that TRPC3 and NALCN are two major leak channels that drive robust pacemaking in nigral DA neurons.

Highlights

Dopamine (DA) neurons in the substantia nigra pars compacta (SNc) are essential for controlling the motivational parts of brain functions such as voluntary movement, action selection, future movement, and reward-based learning (Grace and Bunney, 1984; Schultz, 2007; da Silva et al, 2018)
The main finding from our combined electrical, molecular, immunohistochemical, and pharmacological experiments is that TRPC3 and NALCN channels are two major leak channels essential for the robust pacemaking of SNc DA neurons
SNc DA neurons express a variety of K+, Na+, Ca2+, and nonselective cation channels (NSCCs), and many ion channels and various factors contribute to pacemaking processes (Gantz et al, 2018)

Summary

Introduction

Dopamine (DA) neurons in the substantia nigra pars compacta (SNc) are essential for controlling the motivational parts of brain functions such as voluntary movement, action selection, future movement, and reward-based learning (Grace and Bunney, 1984; Schultz, 2007; da Silva et al, 2018). The dominant view is that, in SNc DA neurons, robust pacemaking depends on leak-like nonselective cation channels that constitutively open at relatively hyperpolarized membrane potentials. The pacemaking of DA neurons is only stopped by SKF-96365 and 2-aminoethoxydiphenyl borate (2-APB), nonspecific blockers for nonselective cation channels (Kim et al, 2007) that are blockers for transient receptor potential-canonical (TRPC) channels (Nilius and Flockerzi, 2014; Lievremont et al, 2005). Among several members of the TRPC family, TRPC3 may be a potential candidate for pacemaker channels in DA neurons because of its constitutive voltage-independent activities at very low membrane potentials (Dietrich et al, 2003; Zhou et al, 2008). NALCN is a Na+permeable nonselective cation channel and, can be a strong candidate for pacemaker channels in DA neurons. In the SNc DA neuron of conditional NALCN knockout (KO) mice, spontaneous firing activity was severely decreased in most cells (Philippart and Khaliq, 2018) implying that NALCN may be an essential channel for pacemaking in SNc DA neurons

Methods

Results

Conclusion