Deficiency in Sleep and Its Affect on the NMDA Glutamate Receptor in Memory
Research has shown that sleep is an important regulator of many human functions, including learning and memory. Without sleep, these regulatory functions are disrupted and can cause problems in a persons' memory ability. A recent research study in St. Paul, Minnesota has shown that internal medicine students deprived of sleep had a reduced working memory capacity (Gohar etal., 2009). These results correlated with an increased risk to making errors during their hospital rotations. In addition, over 3 million Canadians suffered from insomnia or sleep deprivation in 2002 (Statistics Canada, 2002). Thus, with sleep deprivation being so prevalent, it's significant to know the mechanisms of memory regulation in sleep to look at possible treatments in preventing memory loss.
During sleep, neural cells in the hippocampus can navigate, rearrange and strengthen to further stabilize new memories, which creates better accessibility for longer term use (Rauch etal., 2008). This has been theorized as the main mechanism of creating long-term memory. The ability to navigate and strengthen neuronal connections is called synaptic plasticity and is controlled by the changes in the sleep cycle (Benington and Frank, 2003).
The sleep cycle consists of two key phases, REM (rapid eye movement) and non-REM (Benington and Frank, 2003). Both phases are important in memory formation and stabilization, but act very differently. The differences between the two cycles are characterized by their alterations in glutamate receptor activity.
Glutamate receptors are responsible for transferring signals between neurons through intercellular connection points called synapses (Karp, 2010). At the synapse between neurons, the main glutamate receptor involved in the intercellular signalling process is the NMDA glutamate receptor (Mori, 1995). This receptor is both ligand and voltage gated (Mori, 1995). Thus, it must be activated by both a physical interaction with ligands (glutamate and glycine) and an electrical stimulation (Mori, 1995). The electrical response of the synapse is extremely important because it allows for refined control of activation and inactivation of the receptor (Mori, 1995). When activated, the NMDA glutamate receptor acts as a calcium channel (Mori, 1995). Calcium is a very important intracellular messenger that can stimulate many different protein kinases and also affect other cell effectors within the cell (Karp, 2010). Thus, by allowing the transfer of calcium between neurons the NMDA glutamate receptor is a particularly important mediator of neuronal signalling.
During sleep, the activity of NMDA glutamate receptors fluctuate between phases, causing synaptic plasticity. In REM sleep, the glutamate receptor is activated and inactivated rapidly, which has been shown to strengthen synaptic connections, consolidating memory (McDermott etal., 2003). This has also been termed as long term potentiation (LTP). LTP has been seen to have the largest correlation with memory because of its increased activity in sleep after a previous learning experience (McDermott etal., 2003). In comparison, less is known about non-REM sleep, which is associated with long term depression (LTD). Although less is known about LTD it is certain that both phases are necessary to stabilize memories. LTD is characterized by long phases of inactivation and low influxes of calcium ions (Benington and Frank, 2003). It has been theorized that this inactivation is linked with the ability for synapses to move and strengthen, by the probable weakening of older memory traces to further consolidate new memory (Malleret etal., 2010).
Unlike sleep, when a person is awake there is little change in synaptic plasticity because the NMDA glutamate receptors are rapidly activated and receptor activity is similar to REM sleep (McDermott etal., 2003). This means there is a continual activation at the synapse. Thus, with sleep deprivation memories cannot be properly consolidated or strengthened because there is no cycle between LTD and LTP.
Also in sleep deprived individuals, continual activation of NMDA receptors can lead to desensitization of the neural system. The human body contains several regulatory functions that can disable NMDA glutamate receptors if it is malfunctioning or seems overactive (Grady, Bohm, and Bunnett, 1997). These mechanisms include removal of ligands from the extracellular fluid and degradation of the NMDA glutamate receptor. Both of these interactions inhibit any activity at the synapse and can lead to eventual memory loss. Ligand removal is performed by endocytosis of ligands and degradation through lysosomes (Grady etal., 1997). In comparison, degradation of the NMDA receptor is executed through the use of certain endopeptidases that the cell produces (Grady etal., 1997).
If these regulatory functions were turned off temporarily, in theory, the human body may be able to function longer without the need to stabilize memories. One possible treatment is to provide the body with an excess amount of glutamate in order to provide a continual source of ligand to bind to the NMDA receptor. But, glutamate dosages must be carefully watched because too much glutamate can have a neurotoxic potential (Zorumsky and Olney, 1993). This could lead to the eventual cell death of neuronal cells which could create side effects much worse than memory loss. Another theoretical treatment is to prevent the specific endopeptidases from degrading the NMDA receptor. But, disabling endopeptidases theoretically could also create multiple side affects because it could negatively affect the normal recycling of NMDA glutamate receptors.
Upon reviewing the mechanisms of memory and its relationship to sleep deprivation, it was determined that NMDA glutamate receptors played a key role in memory consolidation. Some treatments to improve memory capacity and prevent memory loss for people who have an extended work schedule and insomniacs may be possible. But, although these treatments may have some benefit, the side effects of treatment may be much worse and seem unlikely as a long-term solution to sleep deprivation. Ideally the best way of retaining memory would be to just sleep.
Benington, J. H., & Frank, M. G. (2003). Cellular and molecular connections between sleep and synaptic plasticity. Prog Neurobiol, 69(2), 71-101.
This paper was a review that showed the different phases of the sleeps cycle REM and non-REM, and also compared their physiological differences through long term potentiation and long term depression. It also gave further insight into the actions of glutamate receptors during LTP and LTD.
Gohar, A., Adams, A., Gertner, E., Sackett-Lundeen, L., Heitz, R., Engle, R., et al. (2009). Working memory capacity is decreased in sleep-deprived internal medicine residents. J Clin Sleep Med, 5(3), 191-197.
A study that looks at internal medicine students and provides solid evidence that memory capacity is greatly affected by sleep deprivation, which could lead to errors in practice during hospital rotations.
Grady, E. F., Bohm, S. K., & Bunnett, N. W. (1997). Turning off the signal: mechanisms that attenuate signaling by G protein-coupled receptors. Am J Physiol, 273(3 Pt 1), G586-601.
A review that looks at the mechanisms of many possible regulatory methods, including the removal of ligands and degradation of membrane proteins, in controlling overactive cell signals.
Karp, G. (2010). Cell and Molecular Biology, Concepts and Experiments (6th ed.). Hoboken, N.J.: John Wiley & Sons.
This was used to better understand the use of calcium in the intracellular signalling process and its importance for being transported between cells as well.
Malleret, G., Alarcon, J. M., Martel, G., Takizawa, S., Vronskaya, S., Yin, D., et al. Bidirectional regulation of hippocampal long-term synaptic plasticity and its influence on opposing forms of memory. J Neurosci, 30(10), 3813-3825.
This study analyzes LTDs role in synaptic plasticity thorough PKA mutations in rats. It further theorizes from the activity of glutamate receptors its function to weaken older memories to strengthen newer memory.
McDermott, C. M., LaHoste, G. J., Chen, C., Musto, A., Bazan, N. G., & Magee, J. C. (2003). Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci, 23(29), 9687-9695.
A research article that looks at LTPs role in strengthening synaptic connections through rapid activation of glutamate receptors. It also compares the similarities in glutamate receptor activity in LTP and awake individuals.
Mori, H., & Mishina, M. (1995). Structure and function of the NMDA receptor channel. Neuropharmacology, 34(10), 1219-1237.
A review of mechanisms of NMDA glutamate receptors in the cell membrane an, its specific interaction with ligands and electrical stimulation, and its role in intercellular signalling.
Rauchs, G., Orban, P., Schmidt, C., Albouy, G., Balteau, E., Degueldre, C., et al. (2008). Sleep modulates the neural substrates of both spatial and contextual memory consolidation. PLoS One, 3(8), e2949.
A review of the importance of sleep in modulating changes in synaptic plasticity and the role of inactivation to rearrange synapses for further stabilization.
Statistics Canada. (2005). Insomnia Health Report Retrieved March 20, 2010
Statistics of insomnia rates in Canada for the year of 2002 and a look at its health related problems.
Zorumski, C. F., & Olney, J. W. (1993). Excitotoxic neuronal damage and neuropsychiatric disorders. Pharmacol Ther, 59(2), 145-162.
A look at the neurotoxic ability of glutamate and its possible relation to neurological disorders such as Alzheimer's.
At first I chose to look at sleep and metabolism, but as I started looking for articles I started to have a change in heart. So I decided to look at memory instead. I wanted to be different than other people in the class because I knew most of them were looking at cAMP with respect to memory and sleep. I found a few articles that talked about the NMDA glutamate receptor at the synapse and decided to go with that. A lot of the information was very complicated and I really didn't understand most of the articles I was reading. But I managed to come to some conclusions with the help of the textbook. Definitely the major thing that I learned was how complicated the human brain is and I'm not sure if I'll ever know enough to fully understand its complexity.