Long-term potentiation

138: 996:— in the environment. Since these place fields are distributed throughout the environment, one interpretation is that groups of place cells form maps in the hippocampus. The accuracy of these maps determines how well a rat learns about its environment and thus how well it can navigate it. Tonegawa found that by impairing the NMDA receptor, specifically by genetically removing the NR1 subunit in the CA1 region, the place fields generated were substantially less specific than those of controls. That is, mice produced faulty spatial maps when their NMDA receptors were impaired. As expected, these mice performed very poorly on spatial tasks compared to controls, further supporting the role of LTP in spatial learning. 586:. This is achieved by having a nonsynaptic pool of AMPA receptors adjacent to the postsynaptic membrane. When the appropriate LTP-inducing stimulus arrives, nonsynaptic AMPA receptors are rapidly trafficked into the postsynaptic membrane under the influence of protein kinases. As mentioned previously, AMPA receptors are the brain's most abundant glutamate receptors and mediate the majority of its excitatory activity. By increasing the efficiency and number of AMPA receptors at the synapse, future excitatory stimuli generate larger postsynaptic responses. 741:

potentiation will not be propagated to adjacent synapses. By contrast, global protein synthesis that occurs in the cell body requires that proteins be shipped out to every area of the cell, including synapses that have not received LTP-inducing stimuli. Whereas local protein synthesis provides a mechanism for specificity, global protein synthesis would seem to directly compromise it. However, as discussed later, the synaptic tagging hypothesis successfully reconciles global protein synthesis, synapse specificity, and associativity.

979:. Both groups were then subjected to the water maze spatial memory task. Rats in the control group were able to locate the platform and escape from the pool, while the performance of APV-treated rats was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups, LTP was easily induced in controls, but could not be induced in the brains of APV-treated rats. This provided early evidence that the NMDA receptor — and by extension, LTP — was required for at least some types of learning and memory. 664:(PKMζ), a persistently active kinase whose synthesis increases following LTP induction. PKMζ is an atypical isoform of PKC that lacks a regulatory subunit and thus remains constitutively active. Unlike other kinases that mediate LTP, PKMζ is active not just in the first 30 minutes following LTP induction; rather, PKMζ becomes a requirement for LTP maintenance only during the late phase of LTP. PKMζ thus appears important for the persistence of memory and would be expected to be important in the maintenance of 590:

E-LTP may lead to the synthesis of a "retrograde messenger", discussed later. According to this hypothesis, the newly synthesized messenger travels across the synaptic cleft from the postsynaptic to the presynaptic cell, leading to a chain of events that facilitate the presynaptic response to subsequent stimuli. Such events may include an increase in neurotransmitter vesicle number, probability of vesicle release, or both. In addition to the retrograde messenger underlying presynaptic expression in

737:(the major components of the protein synthesis machinery) in dendrites as early as the 1960s, prevailing wisdom was that the cell body was the predominant site of protein synthesis in neurons. This reasoning was not seriously challenged until the 1980s, when investigators reported observing protein synthesis in dendrites whose connection to their cell body had been severed. More recently, investigators have demonstrated that this type of local protein synthesis is necessary for some types of LTP. 1081: 823:

collective stimulus sufficient to induce LTP (this is explained by the postsynaptic summation of EPSPs described previously). Rather, synaptic tagging explains the ability of weakly stimulated synapses, none of which are capable of independently generating LTP, to receive the products of protein synthesis initiated collectively. As before, this may be accomplished through the synthesis of a local synaptic tag following weak synaptic stimulation.

603: 529: 1032:; that is, inhibitory avoidance training mimicked LTP. In addition, synapses potentiated during training could not be further potentiated by experimental manipulations that would have otherwise induced LTP; that is, inhibitory avoidance training occluded LTP. In a response to the article, Timothy Bliss and colleagues remarked that these and related experiments "substantially advance the case for LTP as a neural mechanism for memory." 326: 310: 318: 302: 521: 22: 971:, a spatial memory task in which rats swim in a pool of murky water until they locate the platform hidden beneath its surface. During this exercise, normal rats are expected to associate the location of the hidden platform with salient cues placed at specific positions around the circumference of the maze. After training, one group of rats had their hippocampi bathed in the NMDA receptor blocker 944: 37:, an important organ for learning and memory. In such studies, electrical recordings are made from cells and plotted in a graph such as this one. This graph compares the response to stimuli in synapses that have undergone LTP versus synapses that have not undergone LTP. Synapses that have undergone LTP tend to have stronger electrical responses to stimuli than other synapses. The term 804:

the same synapse (but not the unstimulated synapse), local protein synthesis creates a short-lived (less than three hours) synaptic tag. The products of gene expression are shipped globally throughout the cell, but are only captured by synapses that express the synaptic tag. Thus only the synapse receiving LTP-inducing stimuli is potentiated, demonstrating LTP's input specificity.

643:(ERK) subfamily of MAPKs—may be the molecular link between E-LTP and L-LTP, since many signaling cascades involved in E-LTP, including CaMKII and PKC, can converge on ERK. Recent research has shown that the induction of L-LTP can depend on coincident molecular events, namely PKA activation and calcium influx, that converge on CRTC1 (TORC1), a potent transcriptional coactivator for 190:(1964) and associates were some of the first researchers to discover long-term potentiation during their work with sea slug Aplysia. They attempted to apply behavioral conditioning to different cells in the slug’s neural network. Their results showed synaptic strength changes and researchers suggested that this may be due to a basic form of learning occurring within the slug. 676:; PKMζ does not play a role in the establishment of short-term memory. PKMζ has recently been shown to underlie L-LTP maintenance by directing the trafficking and reorganization of proteins in the synaptic scaffolding that underlie the expression of L-LTP. Even more recently, transgenic mice lacking PKMζ demonstrate normal LTP, questioning the necessity of PKMζ. 398:(mGluR), while still others depend upon another molecule altogether. The variety of signaling pathways that contribute to LTP and the wide distribution of these various pathways in the brain are reasons that the type of LTP exhibited between neurons depends only in part upon the anatomic location in which LTP is observed. For example, LTP in the 790:

necessary to explain how protein synthesis could occur in the cell body without compromising LTP's input specificity. The synaptic tagging hypothesis attempts to solve the cell's difficult problem of synthesizing proteins in the cell body but ensuring they only reach synapses that have received LTP-inducing stimuli.

454:. Long-term potentiation is only propagated to those synapses according to the rules of associativity and cooperativity. However, the input specificity of LTP may be incomplete at short distances. One model to explain the input specificity of LTP was presented by Frey and Morris in 1997 and is called the 886:

As described previously, the molecules that underlie LTP can be classified as mediators or modulators. A mediator of LTP is a molecule, such as the NMDA receptor or calcium, whose presence and activity is necessary for generating LTP under nearly all conditions. By contrast, a modulator is a molecule

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number, suggesting that L-LTP induces protein synthesis not only in postsynaptic cells, but in presynaptic cells as well. As mentioned previously, for postsynaptic LTP induction to result in presynaptic protein synthesis, there must be communication from the postsynaptic to the presynaptic cell. This

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to the presynaptic fibers. When such a train of stimuli was applied, subsequent single-pulse stimuli elicited stronger, prolonged EPSPs in the postsynaptic cell population. This phenomenon, whereby a high-frequency stimulus could produce a long-lived enhancement in the postsynaptic cells' response to

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in 1966 and has remained a popular subject of research since. Many modern LTP studies seek to better understand its basic biology, while others aim to draw a causal link between LTP and behavioral learning. Still, others try to develop methods, pharmacologic or otherwise, of enhancing LTP to improve

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Different areas of the brain exhibit different forms of LTP. The specific type of LTP exhibited between neurons depends on a number of factors. One such factor is the age of the organism when LTP is observed. For example, the molecular mechanisms of LTP in the immature hippocampus differ from those

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and colleagues reported on a series of experiments that provided perhaps the strongest evidence of LTP's role in behavioral memory, arguing that to conclude that LTP underlies behavioral learning, the two processes must both mimic and occlude one another. Employing an inhibitory avoidance learning

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have implicated synaptic tagging as a mechanism for the input-specificity of LTP. There is some evidence that given two widely separated synapses, an LTP-inducing stimulus at one synapse drives several signaling cascades (described previously) that initiates gene expression in the cell nucleus. At

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Before the local protein synthesis hypothesis gained significant support, there was general agreement that the protein synthesis underlying L-LTP occurred in the cell body. Further, there was thought that the products of this synthesis were shipped cell-wide in a nonspecific manner. It thus became

434:

Owing to its predictable organization and readily inducible LTP, the CA1 hippocampus has become the prototypical site of mammalian LTP study. In particular, NMDA receptor-dependent LTP in the adult CA1 hippocampus is the most widely studied type of LTP, and is therefore, the focus of this article.

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At the end of the 19th century, scientists generally recognized that the number of neurons in the adult brain (roughly 100 billion) did not increase significantly with age, giving neurobiologists good reason to believe that memories were generally not the result of new neuron production. With this

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Cooperativity is observed when two synapses are activated by weak stimuli incapable of inducing LTP when stimulated individually. But upon simultaneous weak stimulation, both synapses undergo LTP in a cooperative fashion. Synaptic tagging does not explain how multiple weak stimuli can result in a

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synapses will in fact undergo LTP. While weak stimuli are unable to induce protein synthesis in the cell body, they may prompt the synthesis of a synaptic tag. Simultaneous strong stimulation of a separate pathway, capable of inducing cell body protein synthesis, then may prompt the production of

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While the above model of E-LTP describes entirely postsynaptic mechanisms for induction, maintenance, and expression, an additional component of expression may occur presynaptically. One hypothesis of this presynaptic facilitation is that persistent CaMKII activity in the postsynaptic cell during

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Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability.... When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or

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One reason for the popularity of the local protein synthesis hypothesis is that it provides a possible mechanism for the specificity associated with LTP. Specifically, if indeed local protein synthesis underlies L-LTP, only dendritic spines receiving LTP-inducing stimuli will undergo LTP; the

622:

in the postsynaptic cell. Two phases of L-LTP exist: the first depends upon protein synthesis, while the second depends upon both gene transcription and protein synthesis. These phases are occasionally called LTP2 and LTP3, respectively, with E-LTP referred to as LTP1 under this nomenclature.

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hippocampus. Bliss and Tony Gardner-Medwin published a similar report of long-lasting potentiation in the awake animal which appeared in the same issue as the Bliss and Lømo report. In 1975, Douglas and Goddard proposed "long-term potentiation" as a new name for the phenomenon of long-lasting

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via the weaker stimulation of many. When one pathway into a synapse is stimulated weakly, it produces insufficient postsynaptic depolarization to induce LTP. In contrast, when weak stimuli are applied to many pathways that converge on a single patch of postsynaptic membrane, the individual

772:

Retrograde signaling is currently a contentious subject as some investigators do not believe the presynaptic cell contributes at all to the expression of LTP. Even among proponents of the hypothesis there is controversy over the identity of the messenger. Early thoughts focused on

814:) is observed when one synapse is excited with LTP-inducing stimulation while a separate synapse is only weakly stimulated. Whereas one might expect only the strongly stimulated synapse to undergo LTP (since weak stimulation alone is insufficient to induce LTP at either synapse), 207: 273:. These experiments were carried out by stimulating presynaptic fibers of the perforant pathway and recording responses from a collection of postsynaptic cells of the dentate gyrus. As expected, a single pulse of electrical stimulation to fibers of the perforant pathway caused 1024:

paradigm, researchers trained rats in a two-chambered apparatus with light and dark chambers, the latter being fitted with a device that delivered a foot shock to the rat upon entry. An analysis of CA1 hippocampal synapses revealed that inhibitory avoidance training induced

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The synaptic tagging hypothesis proposes that a "synaptic tag" is synthesized at synapses that have received LTP-inducing stimuli, and that this synaptic tag may serve to capture plasticity-related proteins shipped cell-wide from the cell body. Studies of LTP in the

711:

number, surface area, and postsynaptic sensitivity to neurotransmitter associated with L-LTP expression. The latter may be brought about in part by the enhanced synthesis of AMPA receptors during L-LTP. Late LTP is also associated with the presynaptic synthesis of

925:

While the long-term potentiation of synapses in cell culture seems to provide an elegant substrate for learning and memory, the contribution of LTP to behavioral learning — that is, learning at the level of the whole organism — cannot simply be extrapolated from

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argues that any difference between associativity and cooperativity is strictly semantic. Experiments performed by stimulating an array of individual dendritic spines, have shown that synaptic cooperativity by as few as two adjacent dendritic spines prevents

576:

group is added to another molecule to change that molecule's activity. Autonomously active CaMKII and PKC use phosphorylation to carry out the two major mechanisms underlying the expression of E-LTP. First, and most importantly, they phosphorylate existing

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plasticity-related proteins, which are shipped cell-wide. With both synapses expressing the synaptic tag, both would capture the protein products resulting in the expression of LTP in both the strongly stimulated and weakly stimulated pathways.

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is directional and proceeds from the presynaptic to the postsynaptic cell. For induction to occur postsynaptically and be partially expressed presynaptically, a message must travel from the postsynaptic cell to the presynaptic cell in a

1127:(Aβ). Aβ exists in both soluble and fibrillar forms. Misprocessing of APP results in the accumulation of soluble Aβ that, according to Rowan's hypothesis, impairs hippocampal LTP and may lead to the cognitive decline seen early in AD. 755:

Retrograde signaling is a hypothesis that attempts to explain that, while LTP is induced and expressed postsynaptically, some evidence suggests that it is expressed presynaptically as well. The hypothesis gets its name because normal

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Even in studies restricted to postsynaptic events, investigators have not determined the location of the protein synthesis that underlies L-LTP. Specifically, it is unclear whether protein synthesis takes place in the postsynaptic

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Upon activation, ERK may phosphorylate a number of cytoplasmic and nuclear molecules that ultimately result in the protein synthesis and morphological changes observed in L-LTP. These cytoplasmic and nuclear molecules may include

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postsynaptic depolarizations generated may collectively depolarize the postsynaptic cell enough to induce LTP cooperatively. Synaptic tagging, discussed later, may be a common mechanism underlying associativity and cooperativity.

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Straube T, Frey JU (2003). "Involvement of beta-adrenergic receptors in protein synthesis-dependent late long-term potentiation (LTP) in the dentate gyrus of freely moving rats: the critical role of the LTP induction strength".

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The pre- and postsynaptic activity required to induce LTP are other criteria by which LTP is classified. Broadly, this allows classification of LTP into Hebbian, non-Hebbian, and anti-Hebbian mechanisms. Borrowing its name from

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techniques necessary for elucidating the biological underpinnings of learning in animals. These skills would not come until the later half of the 20th century, at about the same time as the discovery of long-term potentiation.

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to increase their activity. Second, they mediate or modulate the insertion of additional AMPA receptors into the postsynaptic membrane. Importantly, the delivery of AMPA receptors to the synapse during E-LTP is independent of

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Crary JF, Shao CY, Mirra SS, Hernandez AI, Sacktor TC (April 2006). "Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease".

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in 1949, echoed Ramón y Cajal's ideas, further proposing that cells may grow new connections or undergo metabolic and synaptic changes that enhance their ability to communicate and create a neural network of experiences:

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mechanisms that underlie LTP of the adult hippocampus. The signalling pathways used by a particular cell also contribute to the specific type of LTP present. For example, some types of hippocampal LTP depend on the

277:(EPSPs) in cells of the dentate gyrus. What Lømo unexpectedly observed was that the postsynaptic cells' response to these single-pulse stimuli could be enhanced for a long period of time if he first delivered a 426:

is a type of LTP that does not require such simultaneous depolarization of pre- and postsynaptic cells; an example of this occurs in the mossy fiber hippocampal pathway. A special case of non-Hebbian LTP,

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Frey U, Matthies H, Reymann KG, Matthies H (August 1991). "The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro".

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studies. For this reason, considerable effort has been dedicated to establishing whether LTP is a requirement for learning and memory in living animals. Because of this, LTP also plays a crucial role in

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refers to the observation that when weak stimulation of a single pathway is insufficient for the induction of LTP, simultaneous strong stimulation of another pathway will induce LTP at both pathways.

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Though these theories of memory formation are now well established, they were farsighted for their time: late 19th and early 20th century neuroscientists and psychologists were not equipped with the

362:

model with both biological and experimental justification. Still, others have proposed re-arranging or synchronizing the relationship between receptor regulation, LTP, and synaptic strength.

561:(PKMζ) which does not have dependence on calcium, become autonomously active. Consequently, they are able to carry out the phosphorylation events that underlie E-LTP expression. 3829:

Morris RG, Anderson E, Lynch GS, Baudry M (1986). "Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5".

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Frey U, Krug M, Reymann KG, Matthies H (June 1988). "Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro".

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While the term "long term potentiation" appeared once in the original Bliss and Lømo paper, it was not formally proposed for the phenomenon until the Douglas and Goddard paper.

765:(reverse) direction. Once there, the message presumably initiates a cascade of events that leads to a presynaptic component of expression, such as the increased probability of 1112:

structures. Because of the hippocampus' well established role in LTP, some have suggested that the cognitive decline seen in individuals with AD may result from impaired LTP.

1162:(NAc). Studies have demonstrated that VTA and NAc synapses are capable of undergoing LTP and that this LTP may be responsible for the behaviors that characterize addiction. 660:

such as CREB. ERK-mediated changes in transcription factor activity may trigger the synthesis of proteins that underlie the maintenance of L-LTP. One such molecule may be

169:, he proposed that memories might instead be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. 288:, who joined the Andersen laboratory in 1968, collaborated with Lømo and in 1973 the two published the first characterization of long-lasting potentiation in the 707:

The identities of only a few proteins synthesized during L-LTP are known. Regardless of their identities, it is thought that they contribute to the increase in

2396:"Underlying Mechanisms of Cooperativity, Input Specificity, and Associativity of Long-Term Potentiation Through a Positive Feedback of Local Protein Synthesis" 3077:

Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC (August 2006). "Storage of spatial information by the maintenance mechanism of LTP".

999:

Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. In 1999, Tang

4469: 1970:"Synaptic plasticity in fear conditioning circuits: induction of LTP in the lateral nucleus of the amygdala by stimulation of the medial geniculate body" 1020: 967:

of rats by pharmacologically modifying their hippocampus, a brain structure whose role in spatial learning is well established. Rats were trained on the

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Harris EW, Cotman CW (September 1986). "Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists".

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represents a powerful form of learning and memory. Addiction is a complex neurobehavioral phenomenon involving various parts of the brain, such as the

69:

based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two

340:, protruding structures on dendrites that physically grow and retract over the course of minutes or hours, have suggested a relationship between the 647:(CREB). This requirement for a molecular coincidence accounts perfectly for the associative nature of LTP, and, presumably, for that of learning. 1675:"Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path" 1623:"Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path" 532:

Ca/calmodulin-dependent protein kinase II (CaMKII) appears to be an important mediator of the early, protein synthesis-independent phase of LTP.

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Tang Y, Wang H, Feng R, Kyin M, Tsien J (2001). "Differential effects of enrichment on learning and memory function in NR2B transgenic mice".

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of the spine and the effective synapse strength, due to their relationship with intracellular calcium transients. Mathematical models such as

3239:

Kang H, Schuman EM (September 1996). "A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity".

1011:, had larger LTP and excelled at spatial learning tasks, reinforcing LTP's importance in the formation of hippocampus-dependent memories. 293:

potentiation. Andersen suggested that the authors chose "long-term potentiation" perhaps because of its easily pronounced acronym, "LTP".

3553:"A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis" 3504:"Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage" 679:

The long-term stabilization of synaptic changes is also determined by a parallel increase of pre- and postsynaptic structures such as

546: 443:

NMDA receptor-dependent LTP exhibits several properties, including input specificity, associativity, cooperativity, and persistence.

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Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the

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AD may also impair LTP through mechanisms distinct from Aβ. For example, one study demonstrated that the enzyme PKMζ accumulates in

986:

demonstrated in 1996 that the CA1 area of the hippocampus is crucial to the formation of spatial memories in living mice. So-called

2083:

Yasuda H, Barth AL, Stellwagen D, Malenka RC (January 2003). "A developmental switch in the signaling cascades for LTP induction".

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In addition to the signaling pathways described above, hippocampal LTP may be altered by a variety of modulators. For example, the

639:

brought about by the persistent activation of protein kinases activated during E-LTP, such as MAPK. In fact, MAPK—specifically the

2805:"Influence of actinomycin D, a RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro" 4462: 1731:

Douglas RM, Goddard GV (March 1975). "Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus".

1181: 4395: 4364: 1925:

Ouardouz M, Sastry BR (2000). "Mechanisms underlying LTP of inhibitory synaptic transmission in the deep cerebellar nuclei".

1451: 1222: 644: 640: 607: 2247:"Induction of hebbian and non-hebbian mossy fiber long-term potentiation by distinct patterns of high-frequency stimulation" 614:

Late LTP (L-LTP) is the natural extension of E-LTP. Unlike E-LTP, which is independent of protein synthesis, L-LTP requires

431:

explicitly requires simultaneous presynaptic depolarization and relative postsynaptic hyperpolarization for its induction.

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Lømo T (1966). "Frequency potentiation of excitatory synaptic activity in the dentate area of the hippocampal formation".

4027:

Whitlock JR, Heynen AJ, Shuler MG, Bear MF (August 2006). "Learning induces long-term potentiation in the hippocampus".

3782:"D1/D5 dopamine receptor activation increases the magnitude of early long-term potentiation at CA1 hippocampal synapses" 3355:"Presynaptic protein kinase activity supports long-term potentiation at synapses between individual hippocampal neurons" 4455: 2128:"Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus" 1424: 959:

In 1986, Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories

386:, a prominent LTP researcher, has suggested that LTP may even occur at all excitatory synapses in the mammalian brain. 183:

metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased.

1119:

proposed one model for how LTP might be affected in AD. AD appears to result, at least in part, from misprocessing of

165:

was among the first to suggest a mechanism of learning that did not require the formation of new neurons. In his 1894

4632: 4627: 333:

The physical and biological mechanism of LTP is still not understood, but some successful models have been developed.

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subunit in the hippocampus. The resulting smart mice, nicknamed "Doogie mice" after the fictional prodigious doctor

4728: 4510: 3404:"Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses" 2957:"TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity" 1518:"The historical significance of the discovery of long-term potentiation: an overview and evaluation for nonexperts" 1285:

Bliss TV, Collingridge GL (January 1993). "A synaptic model of memory: long-term potentiation in the hippocampus".

1823:

McEachern JC, Shaw CA (June 1996). "An alternative to the LTP orthodoxy: a plasticity-pathology continuum model".

4723: 4581: 875: 507:, lasting from several minutes to many months, and it is this persistence that separates LTP from other forms of 395: 2756:"Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses" 3402:

Zakharenko SS, Patterson SL, Dragatsis I, Zeitlin SO, Siegelbaum SA, Kandel ER, et al. (September 2003).

137: 913:

activity may also result in the subsequent activation of guanylyl cyclase and PKG. Similarly, activation of

932: 591: 1108:. Much of this deterioration occurs in association with degenerative changes in the hippocampus and other 1176: 750: 1123:(APP). The result of this abnormal processing is the accumulation of fragments of this protein, called 807:

The synaptic tag hypothesis may also account for LTP's associativity and cooperativity. Associativity (

558: 1186: 1120: 1101: 1085: 1049: 407: 352: 4422: 4078:

Bliss TV, Collingridge GL, Laroche S (August 2006). "Neuroscience. ZAP and ZIP, a story to forget".

3930: 3099: 334: 162: 142: 4733: 4718: 4441: 766: 4437: 4387: 3689:"Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus" 902: 406:, an antagonist to the NMDA receptor, which prevented LTP in this pathway. Conversely, LTP in the 4586: 4375: 3025:"Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation" 4622: 4566: 4541: 3094: 2955:

Kovács KA, Steullet P, Steinmann M, Do KQ, Magistretti PJ, Halfon O, et al. (March 2007).

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Wigström H, Gustafsson B (1986). "Postsynaptic control of hippocampal long-term potentiation".

1155: 1131: 1097: 1092:

disrupts LTP and is thought to lead to early cognitive decline in individuals with the disease.

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located in this region become active only when the rat is in a particular location — called a

524:

The early phase of LTP, one model of which is shown here, is independent of protein synthesis.

402:

pathway of the hippocampus is NMDA receptor-dependent - this was proved by the application of

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realization came the need to explain how memories could form in the absence of new neurons.

4675: 4650: 4036: 3942: 3838: 3460: 3303: 3292:"A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites" 3248: 3151: 3086: 2968: 2507: 2352: 2296:"Roles of distinct glutamate receptors in induction of anti-Hebbian long-term potentiation" 1879: 1387: 1294: 1109: 1045: 688: 657: 636: 619: 583: 492: 74: 661: 8: 4665: 4571: 4356: 3551:

Casadio A, Martin KC, Giustetto M, Zhu H, Chen M, Bartsch D, et al. (October 1999).

1134:, which are a pathologic marker of AD. PKMζ is an enzyme with critical importance in the 1041: 845: 799: 508: 478: 415: 399: 278: 81: 4228: 4171: