Proximal dendritic localization of NALCN channels underlies tonic and burst firing in nigral dopaminergic neurons

• Published in: The Journal of physiology 2023-01, Vol.601 (1), p.171-193
• Main Authors: Hahn, Suyun, Um, Ki Bum, Kim, So Woon, Kim, Hyun Jin, Park, Myoung Kyu
• Format: Article
• Language: English
• Subjects: Action Potentials; burst firing; Dopamine; Dopamine - metabolism; Dopamine receptors; dopaminergic neurons; Dopaminergic Neurons - metabolism; Excitability; ion channels; Leak channels; Localization; Mesencephalon; NALCN; Neurons; pacemaker channels; Pacemakers; pacemaking; Substantia nigra; Substantia Nigra - metabolism; tonic firing; TRPC3
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP283716

In multipolar nigral dopamine (DA) neurons, the highly excitable proximal dendritic compartments (PDCs) and two Na+‐permeable leak channels, TRPC3 and NALCN, play a key role in pacemaking. However, the causal link between them is unknown. Here we report that the proximal dendritic localization of NALCN underlies pacemaking and burst firing in DA neurons. Our morphological analysis of nigral DA neurons reveals that TRPC3 is ubiquitously expressed in the whole somatodendritic compartment, but NALCN is localized within the PDCs. Blocking either TRPC3 or NALCN channels abolished pacemaking. However, only blocking NALCN, not TRPC3, degraded burst discharges. Furthermore, local glutamate uncaging readily induced burst discharges within the PDCs, compared with other parts of the neuron, and NALCN channel inhibition dissipated burst generation, indicating the importance of NALCN to the high excitability of PDCs. Therefore, we conclude that PDCs serve as a common base for tonic and burst firing in nigral DA neurons. Key points Midbrain dopamine (DA) neurons are slow pacemakers that can generate tonic and burst firings, and the highly excitable proximal dendritic compartments (PDCs) and two Na+‐permeable leak channels, TRPC3 and NALCN, play a key role in pacemaking. We find that slow tonic firing depends on the basal activity of both the NALCN and TRPC3 channels, but that burst firing does not require TRPC3 channels but relies only on NALCN channels. We find that TRPC3 is ubiquitously expressed in the entire somatodendritic compartment, but that NALCN exists only within the PDCs in nigral DA neurons. We show that NALCN channel localization confers high excitability on PDCs and is essential for burst generation in nigral DA neurons. These results suggest that PDCs serve as a common base for tonic and burst firing in nigral DA neurons. figure legend Cellular organization of NALCN and TRPC3 channels for tonic and burst firing in nigral dopamine (DA) neurons. NALCN and TRPC3 are two major pacemaker channels in nigral DA neurons, and therefore spontaneous tonic firing requires basal activities of both the NALCN and TRPC3 channels. However, synaptically evoked burst firing does not depend on TRPC3 channels but only requires NALCN channels. TRPC3 is ubiquitously expressed in the entire somatodendritic compartment, whereas NALCN is densely localized only within the proximal dendritic compartments (PDCs) in multipolar nigral DA neurons. This NALCN channel localization confer