Two Sides of the Same Coin: Sodium Homeostasis and Signaling in Astrocytes Under Physiological and Pathophysiological Conditions

The intracellular sodium concentration of astrocytes is classically viewed as being kept under tight homeostatic control and at a relatively stable level under physiological conditions. Indeed, the steep inwardly directed electrochemical gradient for sodium, generated by the Na⁺/K⁺-ATPase, contributes to maintain the electrochemical gradient of K⁺ and the highly K⁺-based negative membrane potential, and is a central element in energizing membrane transport. As such it is tightly coupled to the homeostasis of extra- and intracellular potassium, calcium or pH and to the reuptake of transmitters such as glutamate. Recent studies, however, have demonstrated that this picture is far too simplistic. It is now firmly established that transmitters, most notably glutamate, and excitatory neuronal activity evoke long-lasting sodium transients in astrocytes, the properties of which are distinctly different from those of activity-related glial calcium signals. From these studies, it emerges that sodium homeostasis and signaling are two sides of the same coin: sodium-dependent transporters, primarily known for their role in ion regulation and homeostasis, also generate relevant ion signals during neuronal activity. The functional consequences of activity-related sodium transients are manifold and are just coming into view, enabling surprising and important new insights into astrocyte function and neuron-glia interaction in the brain. The present review will highlight current knowledge about the mechanisms that contribute to sodium homeostasis in astrocytes, present recent data on the spatial and temporal properties of activity-related glial sodium signals and discuss their functional consequences with a special emphasis on pathophysiological conditions.