Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.