LAUSR

During cognitive efforts mediated by local neuronal networks, approximately 20% of additional energy is required; this is mediated by chemical messengers such as noradrenaline (NA). NA targets astroglial aerobic glycolysis, the hallmark of which is the end product l‐lactate, a fuel for neurons. Biochemical studies have revealed that astrocytes exhibit a prominent glycogen shunt, in which a portion of d‐glucose molecules entering the cytoplasm is transiently incorporated into glycogen, a buffer and source of d‐glucose during increased energy demand. Here, we studied single astrocytes by measuring cytosolic L‐lactate ([lac]i) with the FRET nanosensor Laconic. We examined whether NA‐induced increase in [lac]i is influenced by: (a) 2‐deoxy‐d‐glucose (2‐DG, 3 mM), a molecule that enters the cytosol and inhibits the glycolytic pathway; (b) 1,4‐dideoxy‐1,4‐imino‐d‐arabinitol (DAB, 300 µM), a potent inhibitor of glycogen phosphorylase and glycogen degradation; and (c) 3‐nitropropionic acid (3‐NPA, 1 mM), an inhibitor of the Krebs cycle. The results of these pharmacological experiments revealed that d‐glucose uptake is essential for the NA‐induced increase in [lac]i, and that this exclusively arises from glycogen degradation, indicating that most, if not all, d‐glucose molecules in NA‐stimulated cells transit the glycogen shunt during glycolysis. Moreover, under the defined transmembrane d‐glucose gradient, the glycolytic intermediates were not only used to produce l‐lactate, but also to significantly support oxidative phosphorylation, as demonstrated by an elevation in [lac]i when Krebs cycle was inhibited. We conclude that l‐lactate production via aerobic glycolysis is an essential energy pathway in NA‐stimulated astrocytes; however, oxidative metabolism is important at rest.