Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis.
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.
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jennifer C
JC
Tudor
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Emily J
EJ
Davis
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lucia
L
Peixoto
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mathieu E
ME
Wimmer
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Erik
E
van Tilborg
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Alan J
AJ
Park
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shane G
SG
Poplawski
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Caroline W
CW
Chung
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Robbert
R
Havekes
Global Statistical Science, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Jiayan
J
Huang
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, INSERM U1104, CNRS UMR7280, 13288 Marseille, France. Institute for Research in Biomedicine (iBiMED) and Aveiro Health Sciences Program, University of Aveiro, 3810-193 Aveiro, Portugal.
Evelina
E
Gatti
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, INSERM U1104, CNRS UMR7280, 13288 Marseille, France. Institute for Research in Biomedicine (iBiMED) and Aveiro Health Sciences Program, University of Aveiro, 3810-193 Aveiro, Portugal.
Philippe
P
Pierre
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA. abele@sas.upenn.edu.
Ted
T
Abel
D000818:Animals; D015153:Blotting, Western; D003071:Cognition; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008569:Memory Disorders / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011691:Puromycin / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D012892:Sleep Deprivation / Q000378:metabolism*; D018709:Statistics, Nonparametric
D003598:Cytoskeletal Proteins; C491255:Eif4ebp2 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D006360:Heat-Shock Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D011691:Puromycin; D000076222:Mechanistic Target of Rapamycin Complex 1