Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila

Abstract

Glucose is the primary source of energy for the brain. However, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production, or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila a glia-to-neuron alanine transfer that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in mushroom body cholinergic neurons to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.