The tired hippocampus: the molecular impact of sleep deprivation on hippocampal function
Introduction
Memory consolidation is the process of storing information in the brain after the initial acquisition. The consolidation of memories consists of two processes, synaptic consolidation and systems consolidation, both of which are modulated by sleep and sleep loss. Synaptic consolidation refers to the growth of new synaptic connections and restructuring of existing synaptic connections, a process that occurs in the first few hours following training. Systems consolidation is usually a slower process and refers to the gradual reorganization of the brain regions that support memory. In this review, we will focus on the molecular underpinnings of synaptic consolidation and highlight more recent studies aimed at defining which alterations in signaling processes are necessary and sufficient to cause the consolidation of hippocampal memories to go awry under conditions of sleep deprivation.
Section snippets
Sleep deprivation affects molecular signaling in the hippocampus that is important for synaptic plasticity
Learning induces a series of molecular events that together contribute to the consolidation of memories at the synaptic level. Calcium entry through NMDA receptors initiates a series of events, including the activation of calcium-dependent adenylate cyclases (Figure 1). The rise in intracellular cAMP levels then leads to the activation of the PKA signaling pathway and phosphorylation of the cyclic AMP-response element binding protein (CREB), a critical regulator of gene transcription [1, 2].
Phosphodiesterases cause memory deficits by degrading cAMP in the hippocampus of sleep-deprived mice
A few hours of sleep deprivation perturbs cAMP-dependent forms of synaptic plasticity such as long-lasting forms of long-term potentiation (LTP) and memory consolidation in tasks that require the hippocampus [8, 16, 22•]. Bath application of hippocampal slices with the PDE4 inhibitor rolipram prevents these deficits in long-lasting forms of LTP in hippocampal area CA1 [16]. Likewise, systemic delivery of rolipram during sleep deprivation made the consolidation of contextual-fear memories
Sleep deprivation attenuates the cAMP-PKA-LIMK pathway leading to spine loss in the hippocampus
Changing the number of dendritic spines and the efficacy of existing spines are an essential component of synaptic plasticity that can occur rapidly after training [31]. To assess whether sleep deprivation affected the LIMK-cofilin pathway in a PDE4A5-dependent fashion, we determined whether sleep deprivation reduced LIMK phosphorylation by PKA, with and without PDE4A5catnull expression. Indeed, sleep deprivation attenuated LIMK phosphorylation by PKA and also reduced cofilin phosphorylation.
Sleep deprivation attenuates translational mechanisms through the mTORC1 pathway
Protein synthesis is essential for hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation [3, 4]. The kinase complex mammalian target of rapamycin (mTOR) complex 1 (mTORC1) regulates protein synthesis through the inhibition of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2). 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
Conclusion and future directions
The recent work highlighted in this review has started to provide a deeper understanding of the causal mechanisms that underlie the impact of sleep deprivation on synaptic consolidation, demonstrating that restoring one of the affected molecular pathways is sufficient to overcome the deficits. These observations, however, also raise further questions. For example, are the observed changes in structural plasticity and translational processes interrelated or are these processes affected by sleep
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank Dr. Sara Aton and Dr. Jennifer Tudor for valuable input on a previous draft of this review and Paul Schiffmacher for help with the illustrations. This work was supported by NIMH grants R21 MH102703 (to T.A., P.I.), R01 MH099544 (to T.A., P.I.), R01 AG 017628 (A.I. Pack, P.I.).
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