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Sleep deprivation is a big problem in modern society and can cause many disorders like insulin resistance, obesity and diabetes and memory loss by altering signalling pathways that the body uses to regulate and keep a homeostatic balance in the cell (Vecsey et al, 2009). The ability to process and retain information is important especially for students and academic personnel and is mediated by neuronal signalling (Longordo et al, 2009). Sleep deprivation can cause a change in cell receptor functionality and neurotransmission which are important in learning, memory and cognition (Longordo et al, 2009). BDNF (brain derived neurotrophic factor) is a mediator molecule that is present between the pre-synaptic and post synaptic membranes and it can bind to and activate TrkB (tropomysin related kinases) (Cunha et al, 2010) which initiates several pathways (Ravassard et al, 2009). BDNF has a crucial role in affecting LTP (long-term potentiation) that is responsible for learning and memory. Lack of sleep alters gene expression and the production of BDNF and therefore it can affect the synaptic potential gradient across the hippocampus of the brain which in turn affects learning and memory (Cunha et al, 2010).
BDNF is synthesised in the neuronal junction from pre-BDNF when it is required by the cell to transmit a signal. Mature mBDNF binds to TkrB in both pre-synaptic and post synaptic membrane causing dimerization of TkrB which results in the activation of several intercellular signalling pathways and it also interacts with other cellular receptors by phosphorylating Fyn (Figure 1) which in turn phosphorylates NMDA-R and opens the channel to allow the entry of Ca2+ into the post synaptic neuron (Cunha et al, 2010). BDNF binding causes a change in ionic gradient in the post synaptic neuron which allows the entry of glutamate via the AMPA-R receptor, so more calcium ions get exchanged enabling LTP of the neuron (Rose et al, 2004).
The influx of Ca2+ results in synaptic strengthening as well as an increase in plasticity of the neuron which means that the neurons can respond quickly and amplify incoming neurotransmission signals (Karp, 2007). This implies that the change in ionic gradient within the post-synaptic neuron is crucial for the process of learning. As a result, impairment of synaptic plasticity or strength can severely affect the ability to process and store information (Romcy-Pereira et al, 2009).
Sleep can re-stabilize and strengthen the synaptic pathways in the brain by resting the receptors like NMDA, AMPAR and TrkB (Romcy-Pereira et al, 2009). Sleep deprivation therefore can affect learning by reducing plasticity and affecting the LTP of the synapses leading to lack of spatial memory and ability to learn (Ravassard et al, 2009). BDNF expression is altered under the conditions of sleep deprivation (Sei et al, 2000). Due to down regulation of BDNF in sleep deprivation, it is easy to follow how the synaptic pathway would be affected. Since BDNF causes TkrB dimerization, lack of that would also lack TkrB dimerization and activation followed by the cascading affect resulting in the failure of TkrB phosphorylating Fyn. This then fails to phosphorylate NMDAR and AMPAR to bring in glutamate and calcium ions resulting in an increase of calcium levels in the cell and weaken the LTP of the nerve cell. Binding of BDNF to TrkB acts as a signal for the synaptic cells to undergo LTP in and increase plasticity (Minichiello, 2009).
Since BDNF acts as a precursor for LTP modulation a lack of BDNF can result in impaired learning and spatial memory (Ravassard et al, 2009; Lee, E., Son, H, 2009)as well as other neuron related disorders. It is found that BDNF deregulation occurs in seizure (where BDNF up-regulated), Alzheimer's, depression (where BDNF down-regulated) and schizophrenia (Lee, E., Son, H, 2009). Therefore it can be concluded that BDNF deregulation can have an immense effect on the emotions of a person but there is no evidence, other than deregulation of BDNF production in depression, that it can regulate emotional state of a person (Lee, E., Son, H, 2009). Depression has also shown to lead in hippocampal degradation, which is responsible for learning and episodic memory (Dere et al, 2010).
The most obvious and relevant therapy for this problem, is obtaining sufficient sleep, allowing the nervous system to recover and build up plasticity. If that is not permitted an individual can suffer from depression and schizophrenia. Antidepressants like fluxotiene and imipramine that ensure adequate BDNF levels can be administered (Dang et al, 2009). Due to BDNF deregulation causing depression most anti depressant drugs are targeted to control the activity or mediate the levels of BDNF in the presynaptic region (Lee, E., Son, H, 2009). Diseases like schizophrenia and Alzheimer's are difficult to control or avoid because they are genetic or age related.
Sleep deprivation can affect synaptic pathways in the brain by altering the amount of BDNF produced which in turn alters the ionic gradient in the post synaptic region (Miniciello, 2009). The most apparent disorder that can occur as a result of BDNF deregulation is depression due to lack of BDNF production control (Lee, E., Son, H, 2009). The simplest way to avoid these is by sleeping properly, that is, a change in lifestyle. One suffering from depression can also potentially opt to pharmaceutical drugs that control BDNF levels like fluxoteine and imipramine or rely on traditional (Dang et al, 2009).
Cunha, C., Brambilla, R., & Thomas, K. L. (2010). A simple role for BDNF in learning and memory? Frontiers in Molecular Neuroscience, 3, 1.
This paper provides a good explanation of BDNF and its role in the synaptic pathway by explaining and illustrating the entire pathway and talking about all the mediating proteins in it.
Dang, H., Chen, Y., Liu, X., Wang, Q., Wang, L., Jia, W., et al. (2009). Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33(8), 1417-1424.
This author does an experiment on mouse with chronic mill stress symptoms which are model animals for studying depression anyway and finds that ginseng administration at a certain dose helps the mice to overcome depression and therefore Ginseng served as a anti-depressant.
Dere, E., Pause, B. M., & Pietrowsky, R. (2010). Emotion and episodic memory in neuropsychiatric disorders. Behavioural Brain Research,
This article talks about the role of hippocampus in memory and also talks about the effect of depression on memory.
Karp, Gerald (2007). Cell and molecular biology: concepts and experiments (5th edition). New Jersey: Wiley J and sons.
Gives a good brief overview of how LTP is associated with the cell`s ionic gradient.
Lee, E., & Son, H. (2009). Adult hippocampal neurogenesis and related neurotrophic factors. BMB Reports, 42(5), 239-244.
They mention that the lack of or excess of BDNF can impair learning abilities by lack of control over the LTP which is responsible for spatial learning and memory.
Longordo, F., Kopp, C., & Luthi, A. (2009). Consequences of sleep deprivation on neurotransmitter receptor expression and function. The European Journal of Neuroscience, 29(9), 1810-1819.
This article gives a good review of how each receptor
Minichiello, L. (2009). TrkB signalling pathways in LTP and learning. Nature Reviews.Neuroscience, 10(12), 850-860.
Another article that basically reiterates the role of BDNF in the synaptic pathway of the cell but the main reference point of this article was TkrB protein and it also had some excellent pictures!
Ravassard, P., Pachoud, B., Comte, J. C., Mejia-Perez, C., Scote-Blachon, C., Gay, N., et al. (2009). Paradoxical (REM) sleep deprivation causes a large and rapidly reversible decrease in long-term potentiation, synaptic transmission, glutamate receptor protein levels, and ERK/MAPK activation in the dorsal hippocampus. Sleep, 32(2), 227-240.
Talks about the different kinds of pathways that BDNF can regulate and what happens in the lack of BDNF.
Romcy-Pereira, R. N., Erraji-Benchekroun, L., Smyrniotopoulos, P., Ogawa, S., Mello, C. V., Sibille, E., et al. (2009). Sleep-dependent gene expression in the hippocampus and prefrontal cortex following long-term potentiation. Physiology & Behavior, 98(1-2), 44-52.
Describes the effect of sleep on the different receptors present on the pre and post synaptic neurons. It also mentions that sleep can allow the system to reinvigorate and give the receptors a chance to rest/
Rose, C. R., Blum, R., Kafitz, K. W., Kovalchuk, Y., & Konnerth, A. (2004). From modulator to mediator: Rapid effects of BDNF on ion channels. BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology, 26(11), 1185-1194.
Another good review article and enhances upon the communication of BDNF and other receptors like AMPAR and NMDAR
Sei, H., Saitoh, D., Yamamoto, K., Morita, K., & Morita, Y. (2000). Differential effect of short-term REM sleep deprivation on NGF and BDNF protein levels in the rat brain. Brain Research, 877(2), 387-390.
Demonstrates how the expression of BDNF is affected in different regions of the brain after sleep deprivation.
Vecsey, C. G., Baillie, G. S., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., et al. (2009). Sleep deprivation impairs cAMP signalling in the hippocampus. Nature, 461(7267), 1122-1125.
This paper demonstrates the link between cAMP and sleep deprivation. It also talks about some of the ways that cell regulation can be used for targeting sleep related disorders.
This paper was rather difficult to write because there were rarely any articles that mentioned the relationship between sleep deprivations and how it affects one thing on the pathway that I was talking about. It was also difficult to find things on how sleep deprivation impairs the pathway and its relationship to physical symptoms the patient experiences. The challenge was mainly to comprehend and make a connection between the several pathways that occur and focus in on one of them and then find specific information regarding defects on that particular pathway because they are all interconnected.