Essay on long-term potentiation

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Long term potentiation (LTP) is believed to be the molecular basis for learning in the brain. Describe the molecular events leading to LTP and evidence that this may be occurring in vivo.

The molecular basis for long term potentiation (LTP) in the brain has been investigated and studied repeatedly as psychologists have tried to understand the basic biological processes involved in learning. Activity-dependent synaptic plasticity is generally accepted as an essential element of memory formation in the brain (Lynch, 2004), and as a result the phenomenon of LTP has received substantial attention: however, there is still considerable debate about the exact mechanisms involved in LTP as well as their t heir relative importance to the process. Fortunately a general consensus has been reached on certain areas and types of LTP, so that it is still possible to use u se the current evidence for LTP to understand the fundamental molecular events that cause LTP to occur. This analysis will firstly attempt to accurately convey the molecular events that lead to LTP and will then move on to discuss the evidence that LTP occurs in vivo and is not merely an artificial concept that has no bearing on the study of learning in living creatures.

It should be noted that this review will focus f ocus primarily on LTP in hippocampal synapses without discussing long term depression (LTD), LTP in other areas of the brain or associative LTP. LTP processes in areas of the brain can vary according to the individual structures and other processes that take place locally: hippocampal LTP has been the most investigated and thus best-understood form of LTP (Lynch, 2004) due to the perceived role of the hippocampus in memory formation, which means that accounts of molecular LTP processes are most applicable to it compared to other, less-studied forms of LTP. The account of LTP given here will be general and elements of it can be applied universally to LTP, but it is intended solely to account for processes at hippocampal synapses. The discussion of evidence for in vivo LTP will discuss evidence for LTP processes in general and should show that studies have collected results that are consistent with LTP theory but that ultimately the process of LTP has not been conclusively demonstrated in vivo.

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LTP begins shortly after the stimulation and associated activity of postsynaptic receptors by glutamate: a-amino-3-hydroxy-5-methyl-4-isoxaz -amino-3-hydroxy-5-methyl-4-isoxazole ole propionic acid (AMPA) receptors bind

glutamate and permit an influx of Na⁺ into the cell through ligand-gated ion channels, and repeated stimulation causes depolarisation of the postsynaptic neuron (Abel and Lattal, 2001). Depolarisation, combined with the presence of glutamate (as observed by coincidence detectors according to Abel and Lattal, 2001), causes the Mg²⁺ block in N methyl-D-aspartate (NMDA) receptors to be released, permitting the influx of Ca²⁺ through   ion channels into the intracellular environment of the postsynaptic neuron (Lynch, 2004).

The influx of Ca²⁺ is a crucial underlying element of LTP and triggers a series of events that lead to increases in synaptic efficiency (Lynch, Muller, Seubert and Larson, 1988). The more immediate effects of the Ca²⁺ inf lux lux will be discussed first, followed by the long-term consequences on the pre- and postsynaptic cells.

The influx of Ca²⁺ activates calmodulin-dependent kinase II (CaMKII) and protein kinase C (PKC): both become phosphorylated and remain activated independently of Ca²⁺ for a period following phosphorylation (Schafe, Nader, Blair and LeDoux, 2001). CaMKII then autophosphorylates a number of other targets, which can include adenylyl cyclase (through G-protein-coupled receptors) and threonine: phosphorylated adenylyl cyclase raises levels of cyclic adenosine monophosphate (cAMP) and thus activates protein kinase A (PKA) (Abel and Lattal, 2001) which phosphorylates cAMP response element binding protein (CREB) (Schafe et al, 2001). The phosphorylated CREB forms complexes with other gene transcription factors, which bind with cAMP-dependent response element (CRE), which mediates gene expression, to promote the creation of new transcriptionally-linked transcriptionally-linked genes and proteins (Abraham and Williams, 2003). The role of these new proteins will be discussed further when looking at the long-term molecular events supporting LTP. Meanwhile, the phosphorylated threonine causes AMPA receptor autophosphorylation, leading to an increased excitatory current into the cell and therefore greater stimulation of NMDA receptors (Schafe et al, 2001). New AMPA receptors re ceptors also appear to be inserted into the postsynaptic membrane, with the insertion associated with NMDA and CaMKII activation: this increases the strength of the response of the postsynaptic cell to glutamate even further (Lynch, 2004). ID: 103211

 

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Simultaneously, a retrograde messenger (possibly nitric oxide produced by binding activated calmodulin to nitric acid synthase, or arachidonic acid) appears to provide feedback to the presynaptic cell, stimulating guanlyl cyclase into producing cyclic guanosine monophosphate (cGMP), which in turn increases the presynaptic output of glutamate (Abraham and Williams, 2003). Other rapid changes brought about by Ca²⁺ influx include the movement of ribosomes into the dendritic spines in preparation for local protein synthesis, the breaking down of adhesion molecules, and the production of synaptic tags at potentiated synapses to allow them to capture newly-produced proteins in the dendritic spines (Abraham and Williams, 2003).

Short-term changes in the presynaptic and postsynaptic p ostsynaptic neurons significantly increase the efficiency of synaptic communication, making the connection between the two neurons stronger. However, this short-term, early-phase LTP (E-LTP) cannot be sufficient for memory formation, as memories often last for more than an hour or so (i.e. longer than the immediate effects of the described events remain active) (Lynch, 2004). For the molecular events forming the basis of long-phase LTP (L-LTP) the synthesis of new n ew proteins and the activity of the adhesion molecules must be examined.

In order for L-LTP to be reached, CREB must be phosphorylated indirectly by phosphorylated adenylyl cyclase (Abel and Lattal, 2001). The formation of new proteins by the influence of CREB and other basic leucine zipper (bZIP) transcription factors on the activity of CRE (and on genes including brain-derived neurotrophic factor (BDNF) and early growth response 1) (Schafe et al, 2001) provides proteins as either raw material or as direction for synaptic augmentation and the creation of new dendritic spine synapses (once picked out by the synaptic tag to ensure growth occurs only at potentiated synapses) (Abraham and Williams, 2003). These proteins provide the basis for widespread morphological changes in the synapse to increase the contact area of the potentiated synapse, with new receptors and enzymes arriving at the synapse following the installation of the structural proteins (Abraham and Williams, 2003). Once the synapse has ceased to be altered proteases are used to break down old adhesion molecules in the synapse so that newly synthesised ones ID: 103211

 

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can be inserted to replace those broken down and to fix the new morphological alterations of the synaptic structure in place (Abraham and Williams, 2003). At this stage the restructuring of the pre- and postsynaptic cells – with the postsynaptic cell undergoing the majority of alterations – is preserved so that the strengthened synapse can continue to function long after the initial induction of its potentiation, forming the basis for L-LTP.

The molecular events that form the basis for hippocampal LTP have been outlined and discussed, but much of the evidence that supports the theory of LTP originates from in vitro  studies on hippocampal slices (Pike, Molden, Paulsen and Moser, 2001). In vivo evidence is required in order to provide support for the theory of LTP and the argument that it is an accurate model for the molecular activity that supports learning.

In vivo evidence for LTP is known to be b e difficult to acquire: it is almost impossible for

experimenters to track individual synapses and monitor them for potentiation when observing the neural activity of a living animal (Pike et al, 2001). This has led research into LTP to focus almost exclusively on synapses in layers removed from the hippocampus (causing disruptive changes in the synapse) and artificial, electrically stimulated potentiation provoked by high frequency stimuli (HFS): this focus has led to arguments that LTP is ‘simply

an artificial way of persuading synapses to alter their strength’ rather than a natural process (Jeffrey, 2001, p. 120). There have, however, been a number of studies that have managed to provide results that do not necessarily prove the existence of LTP in vivo but are consistent with the theory and support it to some extent. Charpier and Deniau (1997) managed to demonstrate that with tetanic stimulation of the facial motor cortex of anesthetised rats LTP could be induced in vivo, and despite their study was of striatal synapses and the artificiality of the experiment the potentiation observed is significant in that it demonstrates that HFS can generate LTP in vivo, even if HFS itself does not occur naturally. The study also demonstrated that striatal LTP seems to be dependent on the availability of calcium in the postsynaptic cell by showing that by exposing calcium to the calcium chelator BAPTA LTP was prevented (Charpier and Deniau, 1997). Schulz, Siemer, Krug and Hollt (1999) investigated the phosphorylation of CREB in vivo in hippocampal LTP ID: 103211

 

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and showed that CREB phosphorylation relied on NMDA receptor activation and that it only occurred when the tetanic stimulation was sufficient to cause non-decremental LTP: their results indicate the importance of CREB transcription factors in L-LTP L -LTP and the link between CREB phosphorylation and persistent potentiation of the hippocampal synapse. s ynapse.

Both studies provide important information about the importance of different elements of LTP in in vivo brain activity, but they are both limited by their use of tetanic stimulation to induce LTP: the criticism remains that HFS is not a realistic way of inducing LTP as it does not appear to occur naturally. Similarly, although Messaoudi, Ying, Kanhema, Croll and Bramham (2002) achieved results that indicate that BDNF can trigger transcriptiondependent L-LTP independently of NMDA activation in vivo the study still relied on tetanic stimulation, undermining the usefulness of the results to in vivo LTP. A more natural experimental method is required to provide strong evidence for LTP. Attempts have been made to produce a natural method of stimulation for LTP experiments: Pike, Meredith, Olding and Paulsen (1999) attempted to mimic naturally occurring theta bursts, which have been linked to L-LTP (Lynch et al, 1988), by using lower-frequency stimuli at 5 Hz and demonstrated that the theta bursts were able to yield synaptic potentiation when pre- and postsynaptic activity coincided. The results of the study suggest that theta bursts may provide a natural form of stimulation that induces LTP without the need for tetanic stimuli and that LTP can occur naturally. However, as the experiment itself does not take place in vivo it needs to be repeated with living subjects so that the real value of theta bursts in

providing evidence for LTP can be assessed. At present there is little evidence that LTP is occurring in vivo, though there is evidence that it can occur in vivo if stimulated artificially and that in this case at least some of the important molecular events of LTP appear to take place as predicted.

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There are a number of complex molecular events that take place in order to produce LTP, and researchers have made substantial progress in understanding these events. Elements of LTP including NMDA activation, Ca²⁺ influx and the phosphorylation of CREB have been demonstrated by in vitro studies of LTP, primarily in hippocampal slices, and these studies have improved the theoretical understanding of LTP as a process. Regrettably, in vivo  evidence for LTP remains scarce: there is some evidence of artificially stimulated LTP taking place in living brains as well as hopes of finding a more natural form of experimental stimulation in theta bursts, but actual in vivo evidence that LTP occurs naturally is rare and appears almost impossible to obtain.

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References - 

Abel, T., and Lattal, K. M. (2001). Molecular mechanisms of memory acquisition, consolidation and retrieval. Current Opinion in Neurobiology, 11, 180-187. Retrieved November 12, 2012, 2012 , from http://www.sciencedirect.com/science/ article/pii/S095943880000194X



Abraham, W. C., and Williams, J. M. (2003). Properties and Mechanisms of LTP Maintenance. The Neuroscientist, 9 (6), 463-474. Retrieved November 12, 2012, 20 12, from http://www.ncbi.nlm.nih.gov/pubmed/14678579



Charpier, S., and Deniau, J. M. (1997). In vivo activity-dependent plasticity at corticostriatal connections: Evidence for physiological long-term potentiation. Proceedings of the National Academies of Sciences, 94 . 7036-7040. Retrieved November 12, 2012,

from http://www.pnas.org/content/94/13/7036.short - 

Jeffrey, K. J. (2001). Plasticity P lasticity of the Hippocampal Cellular Representa Representation tion of Space. In C. Holscher (Ed.), Neuronal Mechanisms of Memory Formation (pp. 100-122). Cambridge: Cambridge University Press.



Lynch, G., Muller, D., Seubert, P., & Larson, J. (1988). Long-Term Potentiation: Persisting Problems and Recent Results. Brain Research Bulletin, 21 . 363-372. Retrieved November 12, 2012, 2012 , from http://www.sciencedirect.com/science/ article/pii/0361923088901487



Lynch, M. A. (2004). Long-Term Potentiation and Memory. Physiological Reviews, 84, 87-136. Retrieved November 12, 2012, from http://physrev.physiology.org/content/84/1/87.full



Messaoudi, E., Ying, S-W., Kanhema, T., Croll, S., & Bramham, C. (2002). BrainDerived Neurotrophic Factor Triggers Transcription-Dependent, Late Phase LongTerm Potentiation In Vivo. The Journal of Neuroscience, 22  (17). 7453-7461. Retrieved November 12, 2012, from http://www.jneurosci.org/content/22/17/7453.short



Pike, F., Meredith, R., Olding, A., & Paulsen, O. (1999). Postsynaptic bursting bursting is

essential for ‘Hebbian’ induction of associative long-term potentiation at excitatory synapses in rat hippocampus. The Journal of Physiology, 518  (2). 571-576. Retrieved

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November 12, 2012, from http://onlinelibrary.wiley.com/doi/10.1111/j.14697793.1999.0571p.x/full - 

Pike, F., Molden, S., Paulsen, O., & Moser, E. I. (2001). Synaptic Potentiation by Natural Patterns of Activity in the Hippocampus. In C. Holscher (Ed.), Neuronal Mechanisms of Memory Formation (pp. 125-136). Cambridge: Cambridge University Press.



Schafe, G. E., Nader, K., Blair, H. T., & LeDoux, Le Doux, J. E. (2001). Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. TRENDS in Neuroscience, 24 (9), 540-546. Retrieved November 12, 2012, from

http://www.ncbi.nlm.nih.gov/pubmed/10974093 - 

Schulz, S., Siemer, H., Krug, M., & Hollt, V. (1999). Direct Evidence for Biphasic cAMP Responsive Element-Binding Protein Phosphorylation during Long-Term Potentiation in the Rat Dentate Gyrus In Vivo. The Journal of Neuroscience, 19 (13). 5683-5692. Retrieved November 12, 2012, from http://www.jneurosci.org/content/19/13/5683.short

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