The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion

Abstract

Persistent neural activity, a sustained circuit output that outlasts the stimuli, underlies shortterm or working memory, as well as various mental representations. Molecular mechanisms that underlie persistent activity are not well understood. Combining in situ whole-cell patch clamping and quantitative locomotion analyses, we show here that the Caenorhabditis elegans neuromuscular system exhibits persistent rhythmic activity, and such an activity contributes to the sustainability of basal locomotion, and the maintenance of acceleration after stimulation. The NALCN family sodium leak channel regulates the resting membrane potential and excitability of invertebrate and vertebrate neurons. Our molecular genetics and electrophysiology analyses show that the C. elegans NALCN, NCA, activates a premotor interneuron network to potentiate persistent motor circuit activity and to sustain C. elegans locomotion. Collectively, these results reveal a mechanism for, and physiological function of, persistent neural activity using a simple animal model, providing potential mechanistic clues for working memory in other systems.

Dopamine Negatively Modulates the NCA Ion Channels inC. elegans

“…Similarly, dop-3 expression in the command interneurons was sufficient to reverse the dop-3 suppression of the slow locomotion of grk-2 mutants (Fig 8G). Given that the fainting phenotypes of nlf-1 mutants and nca mutants were also rescued by expression in command interneurons [43,91], our results suggest that GRK-2, DOP-3, and the NCA channels act in the same neurons. However, we did not see rescue of the grk-2 locomotion phenotype using the glr-1 promoter (Fig 3A), which in principle is also expressed in the command interneurons, and similarly we did not observe statistically significant rescue of the nlf-1 fainting phenotype using the same glr-1 promoter [12].…”

“…In C. elegans, the NCA channels act in premotor interneurons [12,43,91]. To determine whether grk-2 acts in a cell autonomous way to regulate NCA, we identified the head acetylcholine neurons where GRK-2 is expressed.…”

“…In other organisms, mutations in NALCN/NCA or its accessory subunits lead to defects in rhythmic behaviors [16,[34][35][36][37][38][39][40][41][42]. Specifically in C. elegans, the NCA channels act in premotor interneurons where they regulate persistent motor circuit activity that sustains locomotion [43]. In addition to the G q -Rho pathway described above, two other mechanisms have been reported to regulate the activity of the NALCN channel: a G proteinindependent activation of NALCN by G protein-coupled receptors [44,45] and a G proteindependent regulation by extracellular Ca 2+ [46].…”

Na+-Leak Channel, Non-Selective (NALCN) Regulates Myometrial Excitability and Facilitates Successful Parturition

“…Recent studies have shown that NALCN contributes to sustained depolarization and spike trains in interstitial cells of Cajal and hermaphroditespecific neurons in C. elegans [28,37]. Our laboratory also demonstrated that NALCN contributes to the leak current in human myometrium [29].…”

“…Because NALCN lacks several charged residues in the putative voltage-sensing domain, this channel is voltage-insensitive and constitutively active [25]. The Na + leak activity of NALCN is essential for depolarizing the membrane potential, promoting spontaneous firing, and sustaining rhythmic burst activity in other spontaneously active cells [25][26][27][28]. We reported that NALCN is expressed in human myometrial myocytes and contributes to the leak current in myocytes from pregnant women [29].…”