Sleep deprivation

Sleep deprivation (SD) is a lack of sleep commonly found in adolescents and adults (O'Brien, 2009). Because the definition of sufficient sleep varies among many people and cultures, SD can be best defined and recognized by its consequences on a person's daytime task performance and health (O'Brien, 2009). SD negatively affects the cognitive performance of a person, especially in memory and learning (O'Brien, 2009). Understanding of synaptic plasticity in the hippocampus, which is responsible for memory, helps to explain these consequences of SD.

In excitatory synapses, such as those found in the hippocampus, the most common neurotransmitter is glutamate (Genoux & Montgomery, 2007). Glutamate receptors include the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and the N-methyl-d-aspartate receptor (NMDAR; ref Genoux & Montgomery, 2007). Each receptor plays a role in synaptic plasticity, which is the ability of neurons to change synaptic transmission strength in relation to their environment (Fleming & England, 2010). Synaptic plasticity is a result of the regulation and interaction between AMPARs and NMDARs (Genoux & Montgomery, 2007). AMPARs and NMDARs are located in the post-synaptic density (PSD), which is at the tip of the post-synaptic terminal in a neuron (Genoux & Montgomery, 2007). They enter the membrane through exocytosis and then shift laterally into the PSD (Genoux & Montgomery, 2007).

During synaptic transmission before the membrane potential has changed, NMDARs remain inactivated by Mg2+ ions while AMPARs actively respond to glutamate that has been released into the synaptic cleft (Fleming & England, 2010). After active AMPARs trigger an influx of sodium ions that depolarize the cell, NMDARs are activated by the release of the Mg2+ ions and act as channels to allow calcium ions into the neuron (Fleming & England, 2010). The calcium ions are the start of a signalling pathway that will regulate the trafficking of AMPARs to or from the synaptic membrane (Fleming & England, 2010). Rapid stimuli to neurons results in increased trafficking of AMPAR to the membrane while less frequent stimuli result in AMPAR being recycled or degraded after endocytosis back into the neuron (Fleming & England, 2010). The former results in an increase in synaptic strength called long-term potentiation (LTP) while the latter results in a decrease in synaptic strength called long-term depression (LTD) (Fleming & England, 2010). This mechanism describes normal synaptic plasticity in neurons.

However, prolonged stimulation in the hippocampus due to SD can change the synaptic plasticity and affect memory and learning (Longordo, Kopp, & Luthi, 2009). A study of SD in rats showed that in general, lack of sleep initially increases the number of NMDARs and AMPARs in the PSD so as to increase synaptic transmission (Lopez et al., 2008). An increase of NMDAR would mean that more calcium ions enter the post-synaptic area, inducing trafficking of AMPARs to the surface, therefore inducing LTP. However, the results of this study showed that eventually, NR2B subunits, components of NMDAR that are involved in strong currents of transmission, decreased, likely due to homeostatic regulation in the synapses (Lopez et al., 2008). Lower intracellular calcium levels signal for heightened recycling of these glutamate receptors in the PSD, decreasing the amount of AMPAR in the membrane and ultimately lowering synaptic transmission (Lopez et al., 2008). In other words, LTP would initially be induced, but would later be decreased.

This is consistent with the concept of homeostatic plasticity which was first introduced by Turrigiano and colleagues (1998). Their study found that due to prolonged stimuli,synaptic scaling occurs to down-regulate synaptic transmission and to prevent saturation due to constant firing of the neurons (Turrigiano, Leslie, Desai, Rutherford, & Nelson, 1998). This can be explained by desensitization; most glutamate receptors can be activated and desensitized by extracellular glutamate in the synapse (Featherstone & Shippy, 2008). Usually, activation occurs before desensitization does because it is a faster process, but desensitization occurs due to prolonged exposure to high concentrations of glutamate in the synapse (Featherstone & Shippy, 2008). Desensitized receptors undergo conformational changes that signal for their removal from the synaptic membrane, resulting in a reduction of synaptic transmission (Featherstone & Shippy, 2008).

This has implications for people with SD because a lack of sleep means prolonged stimulation of the brain in which synaptic transmission eventually is down-regulated due to desensitization. Weaker synapse strength in the hippocampus, which is responsible for memory and learning, would mean that memory cannot be consolidated properly and that cognitive processing is negatively affected (Longordo et al., 2009). For instance, sleep is needed for visual perceptual and motor skill learning (Walker, 2008).

The most obvious and effective treatment for SD would be to get more sleep, as it would be difficult to prevent the body's natural homeostatic mechanism of synaptic scaling from occurring. A study found that if a subject was sleep-deprived the night of learning a task but rested the night afterwards, it did not improve the person's performance, suggesting that learning and sleep go hand-in-hand (Dang-Vu, Desseilles, Peigneux, & Maquet, 2006). It seems that sleep for memory consolidation is not something that can be compensated for afterwards.

If a treatment was being developed to enhance learning and memory in a sleep-deprived person, it would probably look into ways of re-activating NMDAR after desensitization. As a result of the waking state stimuli, saturation of neuron firing is bound to occur, resulting in a need for homeostatic regulation (Turrigiano et al., 1998). However, if active NMDAR can trigger the trafficking of AMPAR back to the synaptic membrane after desensitization, LTP could be induced again. This treatment would best involve inducing the calcium ion channels in the neurons to open.

All in all, SD has great implications on the health of many people, especially students. A study in rats showed that SD in developing hippocampi resulted in unstable synapses in adulthood (Lopez et al., 2008). Moreover, not only does SD affect memory, but it is correlated to the development of attention-deficit hyperactivity disorder in youth as well as to a negative impact on emotional and behavioural control of people (Dang-Vu et al., 2006). Therefore, awareness of SD and its effects on learning and health needs to be heightened, especially in the student population.

Annotated References:

1. Dang-Vu, T.T., Desseilles, M., Peigneux, P., & Maquet, P. (2006). A role for sleep in brain plasticity. Pediatric Rehabilitation, 9(2), 98-118.

This review article describes details of brain plasticity during different parts of the sleep cycle as well as the effect of SD on task performance.

2. Featherstone, D.E. & Shippy, S.A. (2008). Regulation of Synaptic Transmission by Ambient Extracellular Glutamate. Neuroscientist, 14, 171-181.

This article goes into detail about the cellular and molecular basis of glutamate in synaptic transmission, especially focusing on extracellular ambient glutamate and how its concentration can play a role in desensitization.

3. Fleming, J.J. & England, P.M. (2010). AMPA receptors and synaptic plasticity: a chemist's perspective. Nature Chemical Biology, 6, 89-97.

This review article thoroughly describes the molecular structures of AMPAR and NMDAR as well as the detailed mechanism by which these receptors are involved in synaptic plasticity. It also discusses chemical tools used to study synaptic plasticity.

4. Genoux, D. & Montgomery, J.M. (2007). Glutamate receptor plasticity at excitatory synapses in the brain. Clinical and Experimental Pharmacology and Physiology, 34, 1058-1063.

This article provided a detailed explanation of the roles of AMPAR and NMDAR and how they are trafficked to and from the synaptic membrane. It also describes how the receptors affect the plasticity at excitatory synapses.

5. Longordo, F., Kopp, C., & Lu, A. (2009). Consequences of sleep deprivation on neurotransmitter receptor expression and function. European Journal of Neuroscience, 29, 1810-1819.

This review provided general background information on sleep deprivation and its effects on neurotransmitter receptor function by summarizing the results of various studies that supported this.

6. Lopez, J., Roffwarg, H.P., Dreher, A., Bissette, G., Karolewicz, B., & Shaffery, J.P. (2008). Rapid eye movement sleep deprivation decreases long-term potentiation stability and affects some glutamatergic signaling proteins during hippocampal development. Neuroscience, 153, 44-53.

This study tested LTP in rats by depriving them of rapid eye movement sleep and testing for amounts of glutamate receptor subunits in the cell. It was found that NR2B decreased and it was discussed how NMDAR plays a role in AMPAR trafficking.

7. O'Brien, L.M. (2009). The Neurocognitive Effects of Sleep Disruption in Children and Adolescents. Child and Adolescent Psychiatric Clinics of North America, 18(4), 813-823.

This article reviewed what SD is, its problem in children and adolescents, and how it affects their health, emotional well-being, and task performance.

8. Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C., & Nelson, S.B. (1998). Activity-dependent scaling of quantal amplitude in neo-cortical neurons. Nature, 391, 892-895.

This article suggested homeostatic plasticity by looking at miniature excitatory post-synaptic currents (mEPSC) in rat pyramidal neurons. The results of this study show that after 48 hours of stimuli, mEPSC amplitudes dropped to support the concept of synaptic scaling.

9. Walker, M.P. (2008). Sleep-Dependent Memory Processing. Harvard Review of Psychiatry, 287-298.

This article reviewed the states of sleep and summarized various studies looking into how SD affects different types of learning and of memory consolidation.

Personal Reflection:

I found writing this problem summary more difficult than writing the last one, since I had to learn from scratch how synaptic transmission and plasticity worked and then synthesize information from that new knowledge. The treatment section was also difficult, as there is not a lot of information on that, so I had to apply what I had learnt. However, the topic was intriguing, and now I know why I can't retain information from lectures…

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