Astrocytes generate Na⁺-mediated metabolic waves

Glutamate-evoked Na⁺ increase in astrocytes has been identified as a signal coupling synaptic activity to glucose consumption. Astrocytes participate in multicellular signaling by transmitting intercellular Ca ²⁺ waves. Here we show that intercellular Na⁺ waves are also evoked by activation of single cultured cortical mouse astrocytes in parallel with Ca²⁺ waves; however, there are spatial and temporal differences. Indeed, maneuvers that inhibit Ca²⁺ waves also inhibit Na⁺ waves; however, inhibition of the Na⁺/glutamate cotransporters or enzymatic degradation of extra-cellular glutamate selectively inhibit the Na⁺ wave. Thus, glutamate released by a Ca²⁺ wave-dependent mechanism is taken up by the Na⁺/glutamate cotransporters, resulting in a regenerative propagation of cytosolic Na ⁺ increases. The Na⁺ wave gives rise to a spatially correlated increase in glucose uptake, which is prevented by glutamate transporter inhibition. Therefore, astrocytes appear to function as a network for concerted neurometabolic coupling through the generation of intercellular Na+ and metabolic waves.