Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

Abstract

AbstractThe 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 TNFα controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNFα 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 TNFα 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 TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation.