Neuron-astrocyte metabolic coupling during neuronal stimulation protects against fatty acid toxicity

GRAPHICAL ABSTACT biorxiv;465237v1/UFIG1F1ufig1 HIGHLIGHTSHyperactive neurons generate and release excess peroxidated fatty acids (FAs)Astrocytes endocytose toxic FAs as lipoprotein particles, delivering them to lipid dropletsLipid droplets trigger upregulation of genes involved in metabolism and detoxificationAstrocytes detoxify and consume FAs by mitochondrial oxidation in response to neural activity SUMMARYMetabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic, peroxidated fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by lipoprotein particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial β-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Together, our findings reveal that FA metabolism between neurons and astrocytes is coupled in an activity-dependent manner to protect neurons from FA toxicity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.