Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation

Bryon Silva,Alice Pavlowsky,Alberto Pascual,Olivier L Mantha,Johann Schor,Thomas Preat,Pierre-Yves Plaçais

doi:10.1038/s42255-022-00528-6

Abstract

During starvation, mammalian brains can adapt their metabolism, switching from glucose to alternative peripheral fuel sources. In the Drosophila starved brain, memory formation is subject to adaptative plasticity, but whether this adaptive plasticity relies on metabolic adaptation remains unclear. Here we show that during starvation, neurons of the fly olfactory memory centre import and use ketone bodies (KBs) as an energy substrate to sustain aversive memory formation. We identify local providers within the brain, the cortex glia, that use their own lipid store to synthesize KBs before exporting them to neurons via monocarboxylate transporters. Finally, we show that the master energy sensor AMP-activated protein kinase regulates both lipid mobilization and KB export in cortex glia. Our data provide a general schema of the metabolic interactions within the brain to support memory when glucose is scarce.

Highlights

The main energy source for the brain is glucose[1]
The main model of this metabolic communication is the astrocyte–neuron lactate shuttle (ANLS), wherein glia take up glucose from blood and provide lactate via glycolysis to neurons as an energy substrate; this lactate production is stimulated by neuronal activity[3]
There is no evidence of ketogenesis in neurons[7], several in vitro studies in mammals have shown that astrocytes can synthesize KBs due to their ability to oxidize FAs8,9, suggesting that a system for local production and delivery of KBs could exist inside the brain[10]

Summary

Introduction

The main energy source for the brain is glucose[1]. Metabolic communication between neurons and glia is crucial to sustain brain functions such as memory[2]. There is no evidence of ketogenesis in neurons[7], several in vitro studies in mammals have shown that astrocytes can synthesize KBs due to their ability to oxidize FAs8,9, suggesting that a system for local production and delivery of KBs could exist inside the brain[10]. It is unknown whether glia provide KBs to neurons in vivo to sustain higher brain functions. We showed that KB production and delivery in cortex glia are regulated by AMP-activated protein kinase (AMPK), the cellular master energy sensor, allowing cortex glia to adapt their support to neurons depending on the brain’s energy status

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