Sleep deprivation is a very common problem in today's society. A few hours of sleep lost and its effects kick in. Because of the non-selective nature of sleep deprivation, millions of people are affected by it (Vecsey et al., 2009). As so many individuals are sleep deprived, it is important to understand the negative effects of lost sleep on the body and mind. This paper will focus on the effects of sleep deprivation on memory. In order to understand the connection between sleep deprivation and memory, it is important to know how memory functions in normal conditions, where sufficient amounts of sleep are obtained. In particular, it is necessary to go down to the molecular level and look at the signalling pathways that are associated with memory consolidation and reconsolidation. The focus in this paper will be on the cyclic adenosine monophosphate (cyclic AMP; cAMP) pathway and its downstream effects on memory under normal and sleep deprived conditions.
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Cyclic AMP is a diffusible second messenger that is produced at the plasma membrane. Under normal conditions, the enzyme adenylyl cyclase (AC) converts adenosine triphosphate (ATP) to cAMP (Pavan, Biondi, & Dalpiaz, 2009). G protein-coupled receptors (GPCRs) regulate the levels of cAMP by stimulating these enzymes when specific ligands bind to the receptor (Pavan et al., 2009; Sassone-Corsi, 1995). Once activated, adenylyl cyclase increases the levels of cAMP, which in turn, binds to a subunit of protein kinase A (PKA) and in doing so, releases it. Without the subunit, PKA is activated and released from anchoring sites in the cytoplasm and Golgi complex (Sassone-Corsi, 1995). The freed subunit is a catalytic and phosphorylates the transcription factor cAMP-response element binding protein (CREB) at serine 133 (Won & Silva, 2008). Then, CREB recruits CREB-binding protein (CBP), which is a transcriptional co-activator and CREB dependent transcription begins (Won & Silva, 2008).
One promoter that is targeted in humans is the SLC8A3 promoter (Gabellini, 2004). It is found in neurons and ultimately leads to the translation of NaÂÂ+/Ca2+ exchanger (NCX) proteins that regulate sodium and calcium ion exchange activity (Gabellini, 2004). These promoters have sites for cAMP response elements (CREs) that are regulated by cAMP and also sites for transcriptional repressors and so can be regulated by cAMP (Gabellini, 2004). This suggests that NCX activity plays a large role in regulating Ca2+ balance, which in turn, plays a memory formation (Gabellini, 2004).
The SLC8A3 promoter is just one target of CREB. CREB targets many different kinds of genes and even transcription factors for other, non-CREB dependent genes. These genes lead to various different events. One example is increased neuron excitability; these neurons are easily activated and thus likely play a role in memory representation (Won & Silva, 2004). Won and Silva (2004) also make mention of studies that show over-expression of CREB is linked to an activator of adenylyl cyclase being enhanced and as such, the sensitization of the cAMP pathway by CREB (Won & Silva, 2004). Furthermore, it is noted that CREB may be involved in silencing of synapses in neurons (Won & Silva, 2004). Silenced synapses are ones that express N-methyl-D-aspartate (NMDA), which is considered ideal for storing memory traces (Won & Silva, 2004). Neurons with higher CREB levels would then have more silenced synapses and as such, would be more likely to store memories (Won & Silva, 2004). Although not as researched as CREB's involvement in memory consolidation, it is thought that CREB also plays a role in memory reconsolidation (Won & Silva, 2004). In any case, for both memory consolidation and reconsolidation, the cAMP signalling pathway has a distinct role in its relationship with CREB.
The next question to consider is how this pathway and subsequently, memory, is affected by sleep deprivation. Although the exact function of sleep has not been defined, there are many hypotheses concerning this. One such is that sleep is necessary for brain plasticity in the adult brain; brain plasticity is related to memory (Maquet, 2001). While sleeping, protein synthesis that leads to lasting synaptic modifications in the brain continues and is enhanced (Maquet, 2001). During sleep, there are enhanced levels of acetylcholine (ACh), which acts on muscurinic, a class of receptors (Graves, Pack, & Abel, 2001). Not only is muscurinic, directly involved in memory storage, it can also enhance the synthesis of cAMP (Graves, Pack, & Abel, 2001). With sleep deprivation, these mechanisms are obviously not able to function properly and thus, memory is negatively affected. Furthermore, studies have also shown that during sleep deprivation, cAMP signalling is disrupted by increased levels of phosphodiesterases (PDEs) (Vecsey et al., 2009), which are involved in feedback regulation of cAMP (Conti & Beavo, 2007). PDEs selectively recognize and hydrolyze cAMP and in doing so, interfere with the cAMP signalling pathway in sleep deprived individual more so than is favourable for memory consolidation (Conti & Beavo, 2007).
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Memory is an important function, and with increasing knowledge of the molecular pathways behind memory consolidation, it is seems possible to develop treatments for memory deficit due to sleep deprivation. The most obvious route seems to be one where sleep deprivation is eliminated. However, if that is not an option, research has shown the possibility of drugs that will target PDEs and down-regulate their activity in sleep deprived individuals (Vecsey, 2009). Another option for therapy is to use AC stimulators, such as forskolin, which is inhibited by PDEs (Pavan et al. 2009). As such, research could lead to treatments for memory deficit that affect any point of the cAMP signalling pathway.
In conclusion, cAMP signalling plays a key role in the CREB dependent transcription. This, in turn, has an effect on many genes and mechanisms related to memory consolidation and, possibly, memory reconsolidation. Sleep deprivation negatively influences certain points of this pathway and leads to memory deficit. However, the growing body of knowledge on the mechanisms behind sleep and memory can lead to therapies for memory problems resulting from sleep deprivation.
This assignment involved a lot of reading. The pathway of cAMP involved a lot of extraneous information that I had to sift through. Because of this, the word limit was a definite challenge and this was dealt with by lots of editing. Different papers gave different amounts of detail and sometimes addressed completely different perspectives so it was a challenge trying to figure out what was important and what wasn't. Something I learned from this assignment was synthesizing things together in a much better way. Also, I learned that outlines are a lot more helpful than I thought.
Conti, M., & Beavo, J. (2007). Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signalling. Annual Review of Biochemistry, 76, 481-511.
This paper was used for information on PDEs, which inhibit cAMP synthesis.
Gabellini, N. (2004). Transcriptional regulation by cAMP and Ca2+ links the Na+/Ca2+ exchanger 3 to memory and sensory pathways. Molecular Neurobiology, 30(1), 91-116.
This paper provided a lot of background information on the cAMP pathway, focusing on transcription and a specific example of CREB dependent transcription in the SLC8A3 promoter.
Graves, L., Pack, A., & Abel, T. (2001). Sleep and memory: a molecular perspective, 24(4), 237-243.
This paper talked about the importance of sleep for memory in terms of the molecular pathways that were enhanced during sleep.
Maquet, P. (2001). The role of sleep in learning and memory. Science, 294, 1048-1052.
This paper gave an overview on the different kinds of sleep and why it was necessary to obtain sufficient amounts: brain plasticity.
Pavan, B., Biondi, C., & Dalpiaz, A. (2009). Adenylyl cyclises as innovative therapeutic goals. Drug Discover Today, 14, 982-991.
This paper gave some insight on ACs and therapies that could arise from research about ACs. As well, it provided some background on the cAMP pathway.
Sassone-Corsi, P. (1995). Transcription factors responsive to cAMP. Annual Review of Cell and Developmental Biology, 11, 355-377.
This paper gave very detailed description of the cAMP pathway.
Vecsey, C. G., Baillie, G. S., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., Huang, T., Brown, K. M., Li, X., Descalzi, G., Kim, S. S., Chen, T., Shang, Y., Zhuo, M., Houslay, M. D., Abel, T. (2009). Sleep deprivation impairs cAMP signalling in the hippocampus. Nature, 461, 1122-1129.
This paper highlighted the effect of PDEs in sleep deprived individuals, and also suggested a PDE inhibiting drug treatment.
Won, J. & Silva, A. J. (2008). Molecular and cellular mechanisms of memory allocation in neuronetworks. Neurobiology of Learning and Memory, 89, 285-292.
This paper gave details on connection between CREB and memory.