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Learning and memory are one of the most highly studied areas in neurology, mostly owing to the overlap between neurophysiology and cognitive psychology. A large capacity for research exists because of the highly diverse physiological and psychological consequences of any information gained. Glutamate signalling in the CA1 region of the hippocampus is one of the signal transduction pathways by which learning and memory are developed in the brain. Two post synaptic neural receptors are particularly receptive to glutmate: the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors(AMPARs) and NMDA(N-methyl-D-aspartate) receptor(NMDARs). Of the two, the NMDAR is particularly responsible for the formation of long term potentiation (sustained firing of the neuron) which facilitates memory formation and learning (Lombroso & Ogren, 2009) and this paper will focus primarily on the NMDAR signal transduction pathway.
The molecular basis of learning can be traced back to the functions of NMDAR and AMPAR in the post synaptic membrane and the reaction cascades that ensue. The NMDAR can only be stimulated while the neuron is depolarized (by AMPAR) so that the magnesium plug found in the NMDAR is disolodged, and the glutamate molecule is on the receptor. This allows a rapid influx of calcium ions which attach themselves to the CaMKII (Calcium/calmodulin-dependent kinase II) proteins and activate them to form a 12 unit complex which can then autophosphorylate by the unblocking of a Thr286 on each subunit (Merrill, Chen, Strack, & Hell, 2005). The activation of the 12 membered CaMKII allows it to bind to the NMDA receptor which starts off a cascade involving the recruitment of actin filaments and results in the phosphorylation of the AMPA receptor which is then added to the membrane as seen in Figure 1(J. E. Lisman & Zhabotinsky, 2001).
The movement of AMPAR containing vesicles to the post synaptic membrane and the fusion of the vesicles and subsequent release of the AMPARs continues so that the concentration of AMPARs on the post synaptic membrane increases. This increase in receptors in turn augments the neurons receptivity to glutamate and long term potentiation is thus accomplished as seen in Figure 2(J. E. Lisman & Zhabotinsky, 2001).
The negative effects of sleep deprivation on learning can be attributed to reduction of the number of NMDARs on the post synaptic membrane, diminishing the strength and frequency of the signalling transduction pathway of CaMK II. (Kopp, Longordo, Nicholson, & Luthi, 2006). It has also been found that the NR2A subunit is over expressed in sleep deprived individuals resulting in long-term synaptic depression (Low stimulation of the neuron resulting in decreased post synaptic receptor density)(Longordo, Kopp, Mishina, Lujan, & Luthi, 2009). The NR2A subtype reduces the NMDAR sensitivity to calcium levels outside the neuron and the high ratio of this subtype results in long term synaptic depression and the absence of the NR2A subunit renders the neuron insensitive to sleep deprivation which shows the importance of the NR2A subunit in the neural effects of sleep depression(Longordo, Kopp, Mishina et al., 2009).
Stronger memories are associated with stronger synapses and these synapses are dependent on the presence of NMDA and AMPA receptors. It has been shown that an increase in the expression of AMPA receptors on the post synaptic membrane is one of the ways by which long term potentiation is achieved (Bevilaqua, Medina, Izquierdo, & Cammarota, 2005). The CaMKII pathway initiated by the binding of glutamate to the NMDA receptor increases the density of the AMPA receptor on the post synaptic membrane. This way, the pathway directly builds up long term potentiation and consolidates memory. When an individual is sleep deprived, the activation of the NR2A subunits of the NMDA receptors results in a decreased sensitivity of the NMDR receptors(Longordo, Kopp, & Luthi, 2009). The consistently low stimulation of the NMDA receptor results in a decreased AMPA receptor density on the post synaptic neuron thus resulting in long term depression of the neuron and diminished strength of that particular memory.
Long term depression of synapses resulting from sleep depriviation is reversible and therefore the most effective therapy for the recovery of long term potentiation and memory formation is to get some sleep (Abraham & Williams, 2008). Other potential therapies include the introduction of an enzyme that can alter the NMDA receptor binding site of the NR2A subunit in order to decrease the NR2A-NMDA receptors on the cell membrane therefore sustaining long term potentiation. One of the major problems associated with therapies regarding memory formation is the selectivity of the blood brain barrier and this must be accounted for in order to successfully find a therapy. If such a therapy was found however, it could have huge implications in the treatment of Alzheimers disease, a condition characterized by impairment of learning and memory formation.
Glutmate signalling is only one of the signal transduction pathways involved in memory formation. One of the ways that memory and learning are achieved at the cellular level is through the CaMKII signal transduction pathway and the long term potentiation of the synapse achieved through the increased expression of NMDARs and AMPARs. Sleep deprivation reduces the density of these receptors on the post synaptic membrane and thus diminishes the effectiveness of memory formation. The study of the effects of sleep on the hippocampus is still in its early stages and a lot more research is necessary in order to achieve a thorough understanding of the connection between sleep, learning and memory.
- Abraham, W. C., & Williams, J. M. (2008). LTP maintenance and its protein synthesis-dependence. Neurobiology of Learning & Memory, 89(3), 260-268. This paper showed the reversibility of long term potentiation and depression and thus provided a method of treatment for the detrimental effects of sleep deprivation on learning and memory.
- Bevilaqua, L. R., Medina, J. H., Izquierdo, I., & Cammarota, M. (2005). Memory consolidation induces N-methyl-D-aspartic acid-receptor- and Ca2+/calmodulin-dependent protein kinase II-dependent modifications in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor properties. Neuroscience, 136(2), 397-403. This paper showed long term potentiation as a way that memory formation is achieved.
- Kopp, C., Longordo, F., Nicholson, J. R., & Luthi, A. (2006). Insufficient sleep reversibly alters bidirectional synaptic plasticity and NMDA receptor function. Journal of Neuroscience, 26(48), 12456-12465. This paper showed the effect of sleep deprivation on NMDA receptor function at a molecular level.
- Lisman, J., Schulman, H., & Cline, H. (2002). The molecular basis of CaMKII function in synaptic and behavioural memory. Nature Reviews Neuroscience, 3(3), 175-190. This paper gave insight into the molecular signalling cascade as a result of the CaMKII protein.
- Lisman, J. E., & Zhabotinsky, A. M. (2001). A model of synaptic memory: A CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron, 31(2), 191-201. This paper showed the mechanism by which AMPARs were recruited to the post synaptic membrane.
- Lombroso, P., & Ogren, M. (2009). Learning and memory, part II: Molecular mechanisms of synaptic plasticity. Journal of the American Academy of Child & Adolescent Psychiatry, 48(1), 5-9. This paper provided a general overview about the activation of the NMDAR and its relation to the AMPAR.
- Longordo, F., Kopp, C., & Luthi, A. (2009). Consequences of sleep deprivation on neurotransmitter receptor expression and function. European Journal of Neuroscience, 29(9), 1810-1819. This paper showed the role and mechanism of the NR2A subunit in the reduction of long term potentiation.
- Longordo, F., Kopp, C., Mishina, M., Lujan, R., & Luthi, A. (2009). NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss. Journal of Neuroscience, 29(28), 9026-9041. This paper shows the supreme role that NR2A has on reducing long term potentiation.
- Merrill, M. A., Chen, Y., Strack, S., & Hell, J. W. (2005). Activity-driven postsynaptic translocation of CaMKII. Trends in Pharmacological Sciences, 26(12), 645-653. This paper showed the mechanism for the activation of the CaMKII protein. Personal reflection
- One of the biggest challenges during this assignment was finding relevant information. As this is an ongoing area of research, not very much is known about it and some of those points I was more curious about just did not have enough data. The feedback from the first problem summary really helped as it told me to focus on fulfilling the tasks and not to go off on tangents of my own. The most learning I did from this exercise was the synthesis of information and condensing all I wanted to say so that it fit the word limit.