Cell Reports
Volume 38, Issue 13, 29 March 2022, 110594
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Article
Upregulation of IP3 receptor mediates APP-induced defects in synaptic downscaling and sleep homeostasis

https://doi.org/10.1016/j.celrep.2022.110594Get rights and content
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Highlights

  • APP overexpression causes synaptic hyperexcitability in young flies

  • APP triggers transcriptional activation of IP3R through Dmca1D/CaN/NFAT signaling

  • IP3R upregulation causes defects in both synaptic downscaling and sleep homeostasis

  • Picrotoxin treatment and sleep deprivation alter IP3R expression

Summary

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.

Research topic

CP: Neuroscience

Keywords

synaptic scaling
sleep homeostasis
APP
IP3R
Alzheimer's disease
hyperexcitability

Data and code availability

  • RNA-seq raw and analyzed data have been deposited in the Gene Expression Omnibus (GEO). GEO accession numbers are listed in the key resources table. FPKM, GO and KEGG analyses have also been deposited in Mendeley Data: https://data.mendeley.com/datasets/yrmd2mm37h/1.

  • This study did not generate unique code.

  • Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

Cited by (0)

3

These authors contributed equally

4

Lead contact