Glial Channels and Transporters that Mediate Excretion of K+ in the Microenvironment between Glia and Neurons Shape Neuronal Output in C. elegans

Abstract

Isolated microenvironments, such as the tripartite synapse, where the concentration of ions is regulated independently from the surrounding tissues, exist throughout the nervous system. While the regulation of ions in these microenvironments is known to be mainly mediated by glia, the molecular mechanisms of ion regulation and effects on neuronal output and animal behavior are poorly understood. Using the model system C. elegans, our lab published that Na+ channels of the DEG/ENaC family expressed in glia control neuronal Ca2+ transients and animal behavior in response to sensory stimuli. DEG/ENaC Na+ channels are known to establish a favorable driving force for K+ excretion, which occurs via inward rectifier K+ channels, in epithelial tissues across species. We hypothesized that a similar mechanism exists in the nervous system. Using molecular, genetic, in vivo imaging, and behavioral approaches, we showed that expression in glia of inward rectifier K+ channels and cationic channels rescues the sensory deficits caused by knock-out of glial DEG/ENaCs, supporting our hypothesis. Based on this model, Na+/K+-ATPases are also needed to maintain ionic concentrations following influx of Na+ and excretion of K+. To test this prediction, we used RNAi to knock down each of the 5 α-subunits of the Na+/K+-pump in glia and test the effect of the knock-downs on sensory behavior. We identified Na+/K+-pump α-subunits eat-6 and catp-1 as specifically required in glia for sensory perception, further supporting a model in which glia shapes neuronal output and, consequently, animal behavior by excreting K+ in the microenvironment surrounding neurons. Given that DEG/ENaCs, inward rectifier K+ channels, and Na+/K+-pumps are also expressed in mammalian glia, we propose that this mode of regulation of neuronal function in conserved across species.