Upregulation of IP3 receptor mediates APP-induced defects in synaptic downscaling and sleep homeostasis

Abstract

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 Ca2+-related signaling genes in APP mutants, including genes encoding Dmca1D, calcineurin (CaN) complex, and IP3R. We further demonstrate that increased CaN activity triggers transcriptional activation of Itpr (IP3R) through activating nuclear factor of activated Tcells (NFAT). Strikingly, APP overexpression causes defects in synaptic downscaling and sleep deprivation-induced sleep rebound, and both defects could be restored by inhibiting IP3R. Our findings uncover IP3R 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.