Glial glucose fuels the neuronal pentose phosphate pathway for long-term memory

Brain function relies almost solely on glucose as an energy substrate. The main model of brain metabolism proposes that glucose is taken up and converted into lactate by astrocytes to fuel the energy-demanding neuronal activity underlying plasticity and memory. Whether direct neuronal glucose uptake is required for memory formation remains elusive. We uncover, in Drosophila, a mechanism of glucose shuttling to neurons from cortex glia, an exclusively perisomatic glial subtype, upon formation of olfactory long-term memory (LTM). In vivo imaging reveals that, downstream of cholinergic activation of cortex glia, autocrine insulin signaling increases glucose concentration in glia. Glucose is then transferred from glia to the neuronal somata in the olfactory memory center to fuel the pentose phosphate pathway and allow LTM formation. In contrast, our results indicate that the increase in neuronal glucose metabolism, although crucial for LTM formation, is not routed to glycolysis. [Display omitted] •Neuronal glucose metabolism is increased upon long-term memory formation•Glial cells shuttle glucose to neurons following insulin signaling activation•Glucose fuels the neuronal pentose phosphate pathway Higher brain functions are associated with increased metabolic demand. Through in vivo imaging and behavioral approaches, de Tredern et al. reveal that the neuronal pentose phosphate pathway is crucial for long-term memory formation, supported by glucose transfer from glia to neurons.