Astrocyte influences on neuronal energy supply. Perivascular astrocytes respond to neuronal input (activity) by supplying neurons with substrates for oxidative phosphorylation (lactate, glutamine (Gln)) and glutamate (Glu) replenishment (glutamine), and by signaling changes in local blood flow at the vascular level. Active neurons produce synaptic glutamate that can be taken up by astrocyte glutamate transporters (EAAT) or activate mGluRs. (1) EAAT activation drives electrogenic Na⁺ influx, activates Na⁺/K⁺ ATPases and stimulates glycolytic lactate generation. (2) mGluR activation also leads to glycolysis and lactate production, and neuronal activity drives astrocyte glycogenolysis (3) and eventual lactate formation. Lactate from these three sources is released to the extracellular space via monocarboxylate transporter 1 (MCT1) where it can be taken up by neuronal MCT2 and converted to pyruvate (Pyr) for entry into the TCA cycle (4). Glutamate taken up by astrocyte EAATs can also be converted to glutamine by glutamine synthetase (5). Glutamine can be released and taken up by neuronal amino acid transporters for re-synthesis of glutamate and/or γ-aminobutyric acid via the TCA cycle. For astrocyte changes in blood flow, mGluR activation causes increased Ca²⁺ levels (6), leading to phospholipase A2 (PLA2) activation, arachidonic acid (AA) formation (7) and vasoconstriction following 20-HETE production by cytochrome P450 ω-hydroxylase (8) and continuous prostaglandin E₂ (PGE₂) generation by cyclooxygenase (COX) (9). Vasodilation can result in hypoxic conditions from lactate-mediated inhibition of PGE₂ clearance by prostaglandin transporters (PGT) following PGE₂ diffusion to the vascular smooth muscle (10). EAAT, excitatory amino acid transporter; Pyr, pyruvate.