Upregulation of IP₃ 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 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 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 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.