Hydromineral neuroendocrinology: mechanism of sensing sodium levels in the mammalian brain

Dehydration causes an increase in the sodium (Na) concentration and osmolarity of body fluids. For Na homeostasis of the body, control of Na and water intake and excretion are of prime importance. Although the circumventricular organs (CVOs) were suggested to be involved in body-fluid homeostasis, the system for sensing Na levels within the brain, which is responsible for the control of Na- and water-intake behaviour, has long been an enigma. Na-x is an atypical sodium channel that is assumed to be a descendant of the voltage-gated sodium channel family. Our studies on the Na-x-gene-targeting (Na-x(-/-)) mouse revealed that Na-x channels are localized to the CVOs and serve as a sodium-level sensor of body fluids. As the first step to understand the cellular mechanism by which the information sensed by Na-x channels is reflected in the activity of the organs, we dissected the subcellular distribution of Na-x. Double-immunostaining and immuno-electron microscopic analyses revealed that Na-x is exclusively localized to perineuronal lamellate processes extending from ependymal cells and astrocytes in the organs. In addition, glial cells isolated from the subfornical organ were sensitive to an increase in the extracellular sodium level, as analysed by an ion-imaging method. These results suggest that glial cells bearing Na-x channels are the first to sense a physiological increase in the level of sodium in body fluids, and regulate the neural activity of the CVOs by enveloping neurons. Close communication between inexcitable glial cells and excitable neural cells thus appears to be the basis of the central control of salt homeostasis.