PP2Acα regulates sleep amount and sleep homeostasis in mice

Genetic studies in mice have identified multiple sleep-regulating protein kinases, but the sleep functions of protein phosphatases remain largely unclear. Here, we performed adeno-associated virus-mediated somatic genetics analysis of PP2A catalytic subunits–PP2Acα and PP2Acβ–in sleep regulation in male mice. Adult brain chimeric (ABC) knockout of PP2Acα, but not PP2Acβ, across mouse brain neurons reduces daily amount of rapid eye movement (REM) and non-REM (NREM) sleep, but elevates NREM delta power. Additionally, ABC-PP2AcαKO diminishes and delays homeostatic recovery NREM sleep after sleep deprivation. ABC-expression of wild-type PP2Acα or PP2Acβ, but not methylation deficient mutant PP2Acα, rescues the sleep phenotypes of ABC-PP2AcαΚΟ mice. Moreover, selective knockout of PP2Acα in CaMKII+ or Vglut2+ neurons, but not in mDlx+ or Vgat+ neurons, recapitulates ABC-PP2AcαKO sleep phenotypes. These results identify PP2Acα as a key regulator of sleep amount and sleep homeostasis mainly in the excitatory neurons, and suggest that methylation of PP2Acα is critical for its sleep functions. Adeno-associated virus-mediated somatic genetic analysis identifies the serine/threonine protein phosphatase PP2Acα as a key regulator of both sleep amount and sleep homeostasis in the excitatory neurons of the adult mouse brain.