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-PP2Acα^KO 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-PP2Acα^ΚΟ mice. Moreover, selective knockout of PP2Acα in CaMKII⁺ or Vglut2⁺ neurons, but not in mDlx⁺ or Vgat⁺ neurons, recapitulates ABC-PP2Acα^KO 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.