Metabolic Communication between Astrocytes and Neurons via Bicarbonate-Responsive Soluble Adenylyl Cyclase

Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned 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, which 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. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons. ► Astrocytes express bicarbonate-sensitive soluble adenylyl cyclase (sAC) ► Depolarization and bicarbonate entry increase cAMP in astrocytes ► sAC triggers glycogen breakdown and lactate efflux from astrocytes ► sAC protects synaptic function by lactate efflux from astrocytes Choi et al. show that astrocytes express bicarbonate-sensitive soluble adenylyl cyclase that acts as a metabolic sensor of neuronal activity and supplies lactate derived from glycogen breakdown in astrocytes to maintain neuronal activity when alternative energy sources are needed.