Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis.

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TitleSleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsTudor, JC, Davis, EJ, Peixoto, L, Wimmer, ME, van Tilborg, E, Park, AJ, Poplawski, SG, Chung, CW, Havekes, R, Huang, J, Gatti, E, Pierre, P, Abel, T
JournalSci Signal
Volume9
Issue425
Paginationra41
Date Published2016 04 26
ISSN1937-9145
KeywordsAnimals, Blotting, Western, Cognition, Cytoskeletal Proteins, Enzyme-Linked Immunosorbent Assay, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factor-4G, Eukaryotic Initiation Factors, Heat-Shock Proteins, Hippocampus, Immunohistochemistry, Male, Mechanistic Target of Rapamycin Complex 1, Memory Disorders, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein Biosynthesis, Puromycin, Real-Time Polymerase Chain Reaction, Sleep Deprivation, Statistics, Nonparametric
Abstract

Sleep deprivation is a public health epidemic that causes wide-ranging deleterious consequences, including impaired memory and cognition. Protein synthesis in hippocampal neurons promotes memory and cognition. The kinase complex mammalian target of rapamycin complex 1 (mTORC1) stimulates protein synthesis by phosphorylating and inhibiting the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2). We investigated the involvement of the mTORC1-4EBP2 axis in the molecular mechanisms mediating the cognitive deficits caused by sleep deprivation in mice. Using an in vivo protein translation assay, we found that loss of sleep impaired protein synthesis in the hippocampus. Five hours of sleep loss attenuated both mTORC1-mediated phosphorylation of 4EBP2 and the interaction between eukaryotic initiation factor 4E (eIF4E) and eIF4G in the hippocampi of sleep-deprived mice. Increasing the abundance of 4EBP2 in hippocampal excitatory neurons before sleep deprivation increased the abundance of phosphorylated 4EBP2, restored the amount of eIF4E-eIF4G interaction and hippocampal protein synthesis to that seen in mice that were not sleep-deprived, and prevented the hippocampus-dependent memory deficits associated with sleep loss. These findings collectively demonstrate that 4EBP2-regulated protein synthesis is a critical mediator of the memory deficits caused by sleep deprivation.

DOI10.1126/scisignal.aad4949
Alternate JournalSci Signal
PubMed ID27117251
PubMed Central IDPMC4890572
Grant ListF32 MH099730 / MH / NIMH NIH HHS / United States
T32 NS007413 / NS / NINDS NIH HHS / United States
R21 MH102703 / MH / NIMH NIH HHS / United States
K12 GM081259 / GM / NIGMS NIH HHS / United States
P01 AG017628 / AG / NIA NIH HHS / United States
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