Local differences in baseline sodium shape astrocytic potassium uptake by the NKA

Astrocytes are vital for the maintenance of ion and transmitter homeostasis in the extracellular space, with the inward Na⁺ gradient playing a pivotal role in these processes. Earlier studies not only reported a low baseline Na ⁺ concentration ([Na ⁺ ]) in astrocytes, but also suggested an equilibration of [Na ⁺ ] within the gap-junction-coupled syncytium. This is consistent with the view that the basic homeostatic properties of astrocytes are largely identical due to their critical role in brain function. Here, we used multi-photon fluorescence lifetime imaging for a quantitative determination of astrocytic [Na ⁺ ] in mouse forebrain tissue slices and in vivo . Contrary to the prevailing notion of a rather uniform Na⁺ distribution, we detected a previously unobserved subcellular and cellular heterogeneity in astrocytic [Na ⁺ ], accompanied by differences in the capacity for Na ⁺ /K ⁺ -ATPase (NKA)-mediated uptake of extracellular K ⁺ . Biophysical modelling showed that this heterogeneity can be replicated by the reported differential expression of NKA isoforms in astrocytes together with a different strength of Na ⁺ influx over the plasma membranes. Altogether, our results thus suggest the existence of functionally distinct astrocytes and astrocyte subdomains in which Na ⁺ homeostasis is locally adapted to the specific requirements of surrounding neural networks.