Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis

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 eukaryotic initiation factor 4G (eIF4G) in the hippocampi of sleep-deprived mice. Increasing the abundance of 4EBP2 in hippocampal excitatory neurons prior to 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.

Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory inAplysia

“…Recent research in mice highlighted the role of cyclic adenosine monophosphate signaling pathway 48,100 and the suppression of protein synthesis as a probable mechanism through which sleep deprivation affects the consolidation of long-term memory. 47 However, the mechanisms through which sleep deprivation affects STM or the induction of LTM remain unclear. The current study demonstrated the phylogenetically conserved nature of the necessity of sleep for memory formation outlining the behavioral parameters of the interactions between acute sleep deprivation and STM and LTM in Aplysia.…”

“…[45][46][47][48] In Aplysia, gene expression and protein synthesis after training are necessary for long-term LFI memory. 32,49,50 To determine whether the effect of sleep deprivation on the consolidation of memory is phylogenetically conserved, animals were trained at ZT 11 during the late day, sleep deprived for the first 9 h of the night (ZT 12-ZT 21), and then tested for LTM 24 h after training.…”

The tired hippocampus: the molecular impact of sleep deprivation on hippocampal function

“…Even a brief period of sleep deprivation impacts a wealth of signaling events in the hippocampus including, transcriptional and translational processes [14,15], alterations in second messenger pathways such as the cAMP-PKA signaling pathway [16–18], glutamate receptor composition [19], and synaptic structure [17] (Figure 1). Sleep deprivation even affects gliotransmission [18,20], the release of transmitters from astrocytes (Figure 1).…”

“…Because sleep modulates translational regulators [39], promotes protein synthesis in the rat and primate brain [40,41] as well as in the feline brain mediated by an mTORC1-dependent process [42], a critical question is whether sleep deprivation attenuates translational processes. Indeed, five hours of sleep deprivation reduces protein synthesis, and additional in depth biochemical analyses revealed that sleep deprivation attenuated mTORC1 signaling in the hippocampus [14,15]. …”

New learning while consolidating memory during sleep is actively blocked by a protein synthesis dependent process

“…Similar processes may govern consolidation that immediately follows training, and that during sleep. Memory consolidation and cortical plasticity during sleep are also accompanied by, or is dependent on protein synthesis (Grønli et al, 2013; Rasch and Born, 2013; Seibt et al, 2012; Tudor et al, 2016; Walker, 2005). There is also a general increase in cerebral protein synthesis during sleep phases associated with memory consolidation (Ramm and Smith, 1990).…”