Upregulation of IP receptor mediates APP-induced defects in synaptic downscaling and sleep homeostasis.

Evidence suggests that impaired synaptic and firing homeostasis represents a driving force of early Alzheimer's disease (AD) progression. Here, we examine synaptic and sleep homeostasis in a Drosophila model by overexpressing human amyloid precursor protein (APP), whose duplication and mutations cause familial early-onset AD. We find that APP overexpression induces synaptic hyperexcitability. RNA-seq data indicate exaggerated expression of Ca-related signaling genes in APP mutants, including genes encoding Dmca1D, calcineurin (CaN) complex, and IPR. We further demonstrate that increased CaN activity triggers transcriptional activation of Itpr (IPR) through activating nuclear factor of activated T cells (NFAT). Strikingly, APP overexpression causes defects in synaptic downscaling and sleep deprivation-induced sleep rebound, and both defects could be restored by inhibiting IPR. Our findings uncover IPR as a shared signaling molecule in synaptic downscaling and sleep homeostasis, and its dysregulation may lead to synaptic hyperexcitability and AD progression at early stage.