Microglial TNF alpha orchestrates protein phosphorylation in the cortex during the sleep period and controls homeostatic sleep

Sleep intensity is adjusted by the length of previous awake time, and under tight homeostatic control by protein phosphorylation. Here, we establish microglia as a new cellular component of the sleep homeostasis circuit. Using quantitative phosphoproteomics of the mouse frontal cortex, we demonstrate that microglia-specific deletion of TNF alpha perturbs thousands of phosphorylation sites during the sleep period. Substrates of microglial TNF alpha comprise sleep-related kinases such as MAPK5 and MARKs, and numerous synaptic proteins, including a subset whose phosphorylation status encodes sleep need and determines sleep duration. As a result, microglial TNF alpha loss attenuates the build-up of sleep need, as measured by electroencephalogram slow-wave activity and prevents immediate compensation for loss of sleep. Our data suggest that microglia control sleep homeostasis by releasing TNF alpha which acts on neuronal circuitry through dynamic control of phosphorylation.