Sleep deprivation impairs cAMP signalling in the hippocampus

Abstract

Millions of people regularly obtain insufficient sleep1. Given the impact of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning paradigms that are dependent on the hippocampus2–5. In this study, we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired cAMP/PKA-dependent forms of synaptic plasticity6 in the hippocampus, reduced cAMP signaling, and increased activity and protein levels of phosphodiesterase-4 (PDE4), an enzyme that degrades cAMP. Treatment with PDE inhibitors rescued the sleep deprivation-induced deficits in cAMP signaling, synaptic plasticity, and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signaling through increased PDE4 activity. Thus drugs that enhance cAMP signaling may provide a novel therapeutic approach to counteract the cognitive effects of sleep deprivation.

The impact of sleep loss on hippocampal function

“…However, these differences in subunit ratios and mediated current after sleep deprivation have not been observed by other research groups. After 5 h of sleep deprivation by the gentle handling procedure (Ledoux et al 1996), no difference was observed in NMDA receptor-mediated current or in the NMDA/AMPA receptor ratio in CA1 (Vecsey et al 2009). These differences in NMDA receptor-mediated current could be attributed to sleep-deprivation techniques used in these two experimental designs.…”

“…The NR2B subunit of the NMDA receptor has also been observed to decrease in the hippocampus as a result of REM sleep deprivation (Lopez et al 2008;Park et al 2012). Although both of these studies observed clear differences in trafficking and NMDA receptor-mediated current using extended periods of sleep deprivation, these findings conflict with findings from briefer periods of sleep deprivation (Vecsey et al 2009). Using electron microscopy, Kopp and colleagues found that 4 h of sleep deprivation by exposure to a novel environment and introduction to new nesting material increased the NR2A/NR2B NMDA-receptor subunit ratio as well as total NR2A subunits in the hippocampus (Kopp et al 2006;Longordo et al 2009).…”

“…Work from our research group demonstrated that acute sleep deprivation by gentle handling specifically disrupted LTP requiring cAMP signaling. Our group went on to show that the LTP deficit induced by sleep deprivation could be rescued by increasing cAMP signaling (Vecsey et al 2009). More recent work showed that LTP was resistant to sleep deprivation if extracellular adenosine was attenuated either using a pharmacological approach or a genetic approach (Alhaider et al 2010a;Florian et al 2011).…”

“…Extended periods of sleep deprivation for 24-72 h appear to eliminate or reduce LTP induction in vitro (Campbell et al 2002;McDermott et al 2003). However, brief periods of sleep deprivation only appear to disrupt signaling underlying LTP maintenance while induction remains intact (Vecsey et al 2009;Florian et al 2011). No studies have specifically examined the time course of sleep deprivation to impair LTP.…”

Neuroscience and education: prime time to build the bridge

“…These findings close a causal loop that relates mnemonic gain to early-sleep neural synchronization. Animal studies have demonstrated that sleep triggers mnemonic reverberation at the level of action potentials 20 as well as calcium-dependent molecular events related to long-term memory storage 21,22 .…”