Astrocytes participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. Glycogen stores are unique to astrocytes in the brain and are concentrated in astrocyte processes surrounding synaptic terminals. We have investigated the molecular pathways responsible for metabolic coupling between neuronal activity and astrocytes in the hippocampus region of the brain. We discovered that a bicarbonate (HCO3-) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO3- entry via the electrogenic NaHCO3 cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space. During periods of low glucose, lactate is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of [K+]ext and also during aglycemic episodes, helping to maintain synaptic function. The mobilization of glycogen and lactate efflux from astrocytes may also lead to alterations of neurovascular coupling as lactate enhances the efficacy of the astrocyte mediated vasodilation pathway. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons. Depletion of the glycogen reservoir in astrocytes may lead to metabolic stress and synaptic impairment when glucose levels or supply are compromised.