Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep.
The time we spend asleep is adjusted to previous time spent awake, and therefore believed to be under tight homeostatic control. Here, we establish microglia as a new cellular component of the sleep homeostat circuit. By using quantitative phosphoproteomics we demonstrate that microglia-derived TNF controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNF comprise sleep-promoting kinases and numerous synaptic proteins, including a subset whose phosphorylation status codes sleep need and determines sleep duration. As a result, lack of microglial TNF attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNF that acts at the neuronal circuitry through dynamic control of phosphorylation.