Glial Na_x Channels Control Lactate Signaling to Neurons for Brain [Na⁺] Sensing

Sodium (Na) homeostasis is crucial for life, and Na levels in body fluids are constantly monitored in the brain. The subfornical organ (SFO) is the center of the sensing responsible for the control of salt-intake behavior, where Na_x channels are expressed in specific glial cells as the Na-level sensor. Here, we show direct interaction between Na_x channels and α subunits of Na⁺/K⁺-ATPase, which brings about Na-dependent activation of the metabolic state of the glial cells. The metabolic enhancement leading to extensive lactate production was observed in the SFO of wild-type mice, but not of the Na_x-knockout mice. Furthermore, lactate, as well as Na, stimulated the activity of GABAergic neurons in the SFO. These results suggest that the information on a physiological increase of the Na level in body fluids sensed by Na_x in glial cells is transmitted to neurons by lactate as a mediator to regulate neural activities of the SFO.