Sleep Deprivation and cAMP
Over the past century average sleep duration has decreased significantly. In 1910 people were averaging around 9hours of sleep a night, this has decreased to around 7.5 hours currently (Webb & Agnew, 1975). Chronic sleep deprivation is becoming normal for millions of people. Until recently most researchers believed this would have little adverse affect on the body. Some papers even suggested the body could get accustomed to lack of sleep and function completely normally, without any mood or changes in energy levels (Friedmann et al., 1977). Contrary to this, researchers have begun to notice multiple bodily functions that often become less efficient under sleep deprivation. One function affected by sleep deprivation is cell signaling. The impairment of cell signaling is particularly interesting because the downstream effects can be severe. Understanding the mechanism behind the development of these problems is essential if we are to understand the dangers of sleep deprivation and develop effective treatments.
Cell signaling is particularly important in the formation of memory. Researchers generally believe memories are formed by the modification of synaptic strength (Bliss & Collingwood, 1993). Synaptic strength is the change in transmembrane potential caused by the flow of ionic current through postsynaptic ionic channels. Stimulation of postsynaptic neurotransmitter receptors results in modifications to transmembrane potential. These changes are often short term, lasting from several seconds to minutes. However repeated exposure can lead to permanent changes in the synaptic strength. With repeated exposure secondary molecules involved in cell signaling like cyclic adenosine monophosphate (cAMP) can initiate protein synthesis resulting in permanent changes to the synapse itself. This process is called long-term potentiation (LTP). Effective LTP is essential for learning and memory formation. There are multiple mechanisms that lead to LTP. Two of the main forms of LTP, paced 4-train simulation, and theta-burst stimulation depend on cell signaling by cAMP (Vecsey et al., 2009).
Sleep deprivation has been shown to impair cAMP signaling in the hippocampus (Vecsey et al., 2009). Using mice Vecsey et al. demonstrated long-term maintenance of LTP was impaired due to decreased cAMP signaling when the mice had been sleep deprived (Vecsey et al., 2009). One of the downstream targets for cAMP is the cAMP recponsive element binding protein (CREB). CREB is a nucleur transcription factor, it promotes the transcription of cAMP responsive genes (Josselyn & Nguyen, 2005). Under normal conditions cAMP phosphorylates Ser 133 of CREB, resulting in the activation of CREB. Sleep deprivation causes decreased phosphorylation in the CA1 and dentate gyrus regions of the hippocampus (Vecsey et al., 2009). This decreases the activation of CREB resulting in decreased LTP. The decrease in phosphorylation is due to a decrease in cAMP levels (Vecsey et al., 2009). cAMP can be degraded by a group of enzymes called cyclic nucleotide phosphodiesterases (PDEs). Vescey et al. found that cAMP breakdown by PDE4 was increased in sleep deprived mice. This results in lower levels of cAMP, and presumably causes lower levels of CREB activation due to lower levels of phosphorylation by cAMP. The increase in PDE4 causes higher levels of cAMP breakdown making it difficult to obtain the threshold cAMP level required for successful cAMP sensitive LTP.
Decreased LTP due to sleep deprivation harms the ability to form memories. Long term potentiation is an integral part of synaptic plasticity, it is believed to be the basis for learning and memory. Learning and memory formation are essential to mental and overall human health. The changes in cell signaling due to sleep deprivation may seem small, but they have major detrimental effects on memory formation, and thus overall human health. Understanding the mechanisms of cell signaling in LTP provides information that can help us combat neurological disorders, as well as finding effective treatments for sleep deprivation.
The Treatment of sleep deprivation is a complicated issue. Obviously the ideal treatment would be for the patient to simply get more sleep, stopping them from being sleep deprived. However, often this is not an option. People become sleep deprived for a number of different reasons, from shift work, to sleeping problems or disorders, to frequent travel and jet lag. Whatever the reason the increasing number of people affected by sleep deprivation warrants the development of treatment.
Vescey et al. had success treating decreased LTP with rolipram. Rolipram is an inhibitor selective for PDE4. Rolipram inhibits the action of PDE4 stopping the high levels of cAMP degradation that results in poor LTP. When sleep deprived mice were given rolipram normal levels of LTP were observed (Vecsey et al., 2009). This suggests that development of drugs that stop the activity, expression or targeting of PDE4 could help combat the decreased LTP caused by sleep deprivation.
Understanding the mechanisms discussed in this paper has uses on a greater scale. Many neurological disorders, for example Alzheimer's disease involve LTP. Understanding more about the multiple different pathways involved in LTP will likely lead to a better understanding of why neurological conditions develop, and allow us to find more effective treatments. Cell signaling research has implications not only in health. It is essential to understanding drug addiction, a problem that has major societal implications.
Cell signaling is essential for good health. SLepp deprivation has detrimental effects on cell signaling. In particular sleep deprivation can cause decreased levels of cAMP in several regions of the hippocampus that are important in memory formation. This results in lower than usual LTP, resulting in impaired learning and memory formation. This is a consequence that affects the entire organism. Understanding the mechanisms behind cell signaling can help us develop treatments and unravel the inner workings of the human brain.
Webb W.B., & Agnew H.W. (1975) Are we chronically sleep deprived?. Psychonomic Bulletin & Review, 6, 47-48
This reference provided an interesting fact to start the essay, it illustrated the change in average sleep patterns.
Freidmann J., Globus G., Huntley A., Mullaney D., Naitoh P., Johnson L. (1977) Performance and mood during and after gradual sleep reduction. Psychophysiology, 1977, 14, 245-50.
This reference just showed the older belief, that sleep deprivation had little effect.
Vecsey C.G., Baillie G. S., Jaganath D., Havekes R., Daniels A., et al. (2009) Sleep deprivation impairs cAMP signalling in the hippocampus. Nature, 461, 1122-1125
This was my main reference, it told me almost everything I needed to know.
Josselyn S. A., Nguyen P. V., (2005) CREB, Synapses and memory disorders: past progress and future challenges. Current Drug Targets-CNS & Neurological Disorders, 4, 481-497
This reference taught me a bit more about how synapses work, and the function of CREB.
Bliss T.V., Collingridge G.L. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361, 31-399.
This reference described how LTP helps in memory formation.
This paper taught me a lot about memory formation and how the brain works. This was a very interesting paper to write. I found it difficult to get started at first, I was going to do one of the other cell signals, but finding good research papers was very difficult. It is ironic how I feel very sleep deprived as I submit this paper.