Locus Coeruleus Neurons’ Firing Pattern Is Regulated by ERG Voltage-Gated K+ Channels

Abstract

Locus coeruleus (LC) neurons, with their extensive innervations throughout the brain, control a broad range of physiological processes. Several ion channels have been characterized in LC neurons that control intrinsic membrane properties and excitability. However, ERG (ether-à-go-go–related gene) K+ channels that are particularly important in setting neuronal firing rhythms and automaticity have not as yet been discovered in the LC. Moreover, the neurophysiological and pathophysiological roles of ERG channels in the brain remain unclear despite their expression in several structures. By performing immunohistochemical investigations, we found that ERG-1A, ERG-1B, ERG-2 and ERG-3 are highly expressed in the LC neurons of mice. To examine the functional role of ERG channels, current-clamp recordings were performed on mouse LC neurons in brain slices under visual control. ERG channel blockade by WAY-123,398, a class III anti-arrhythmic agent, increased the spontaneous firing activity and discharge irregularity of LC neurons. Here, we have shown the presence of distinct ERG channel subunits in the LC which play an imperative role in modulating neuronal discharge patterns. Thus, we propose that ERG channels are important players behind the changes in, and/or maintenance of, LC firing patterns that are implicated in the generation of different behaviors and in several disorders.

Sex differences in single neuron function and proteomics profiles examined by patch‐clamp and mass spectrometry in the locus coeruleus of the adult mouse

“…These channels play a critical role in determining the characteristics of the action potential after‐hyperpolarization, which in turn influences the rate at which the neuron can fire subsequent action potentials 31 . Although the duration of the action potential after‐hyperpolarization was shorter in neurons from male mice compared to female mice, this difference was pronounced but did not reach statistical significance 31,32 …”

“…31 Although the duration of the action potential afterhyperpolarization was shorter in neurons from male mice compared to female mice, this difference was pronounced but did not reach statistical significance. 31,32 F I G U R E 6 Pathway analysis in PC/SCP Neurons from female and male mice. (A) Most significant networks of differentially expressed proteins in PC/SCP neurons across sexes.…”

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

“…This area is related to cognition, learning and memory, among other roles (Uematsu et al, 2017;James et al, 2021;Dahl et al, 2022). This channel prevents increased firing rate and discharge irregularities in those LC neurons (Hasan et al, 2022). In PD, the LC neurons degeneration is present before DAergic neurons degeneration.…”