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An example of long-term potentiation (LTP). The graph illustrates the analysis of a single field potential recording from a rat hippocampal slice. The inset shows the placement of the stimulating and recording electrode within the slice, and above, two raw traces of EPSP field potentials before and after tetanic stimulation. Field potentials were evoked by stimulation of Schaffer collaterals and recorded in stratum radiatum of the hippocampal slice (i.e. the Schaffer collateral/CA1 synapses). The individual points on the graph each represent the measurement of the rising slope of one EPSP field potential. Black squares indicate the measurements taken before tetanic stimulation. The green squares are measurements taken immediately after tetanic stimulation (PTP or post-tetanic potentiation) while the blue squares are measurements taken between 3 and 60 minutes after tetanization (LTP or long-term potentiation). Test stimuli were administered once every 30 sec. Tetanic stimulation was the test stimulus given at 100 Hz for 1 sec. Note how the amplitude of the EPSP field settles into a new, more elevated level after tetanic stimulation.]]

In neuroscience, long-term potentiation (LTP) is an increase in the chemical strength of a synapse that lasts from minutes to several days.[1] It has been observed both in cultured cells (in vitro) and in living animals (in vivo). In cultured cells, applying a series of short, high-frequency electric stimuli to a synapse can strengthen, or potentiate, the synapse for minutes to hours. In living cells, LTP occurs naturally and can last from hours to days, months, and years. Neurons connected by a synapse that has undergone LTP have a tendency to be active simultaneously: after a synapse has undergone LTP, subsequent stimuli applied to the presynaptic cell are more likely to elicit action potentials in the postsynaptic cell.

Though its biological mechanisms have not yet been fully determined, LTP is believed to contribute to synaptic plasticity in living animals, providing the foundation for a highly adaptable nervous system. Because changes in synaptic strength are thought to underlie memory formation, LTP is believed to play a critical role in behavioral learning. In fact, most neuroscientific learning theories regard long-term potentiation and its opposing process, long-term depression, as the cellular bases of learning and memory.

LTP was discovered in the mammalian hippocampus by Terje Lømo in 1966 and has remained a popular subject of neuroscientific research since. Most modern LTP studies seek to better understand its biology, while other research aims to develop drugs that exploit these biological mechanisms to treat neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In fact, several investigators routinely use LTP experimental paradigms in combination with animal models of trauma, Alzheimer's disease, and/or epilepsy, for example,[2] in order to investigate how synaptic plasticity might be altered by disease or injury.

Contents

[edit] History

[edit] Early theories of learning

The 19th century neuroanatomist Santiago Ramón y Cajal proposed that memories might be stored in the connections between nerve cells.
The 19th century neuroanatomist Santiago Ramón y Cajal proposed that memories might be stored in the connections between nerve cells.

By the end of the 19th century, scientists generally recognized that the number of neurons in the adult brain (roughly 1011) did not increase significantly with age, giving neurobiologists good reason to believe that memories were generally not the result of new nerve cell production.[3] With this realization came the need to explain how memories could form in the absence of new nerve cells.

Among the first neuroscientists to suggest that learning was not the product of new cell growth was the Spanish neuroanatomist Santiago Ramón y Cajal. In his 1894 Croonian Lecture, he proposed that memories might be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication.[3] Hebbian theory, introduced by Donald Hebb in 1949, echoed Ramón y Cajal's ideas, and further proposed that cells may grow new connections between each other to enhance their ability to communicate:

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 metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased.[4]

Though these theories of memory formation are now well established, they were foresighted for their time: late 19th and early 20th century neuroscientists were not equipped with the neurophysiological techniques necessary for elucidating the biological underpinnings of learning in animals. These skills would not come until the latter half of the 20th century, at about the same time as the discovery of long-term potentiation.

[edit] Discovery of long-term potentiation

LTP was first discovered in the rabbit hippocampus. In humans, the hippocampus is located in the medial temporal lobe. This image of the underside of the human brain shows the hippocampus highlighted in red. The frontal lobe is at the top of the image and the occipital lobe is at the bottom.
LTP was first discovered in the rabbit hippocampus. In humans, the hippocampus is located in the medial temporal lobe. This image of the underside of the human brain shows the hippocampus highlighted in red. The frontal lobe is at the top of the image and the occipital lobe is at the bottom.

LTP was first observed by Terje Lømo in 1966 in the Oslo, Norway, laboratory of Per Andersen.[1] There, Lømo conducted a series of neurophysiological experiments on anesthetized rabbits to explore the role of the hippocampus in short-term memory.

Isolating the connections between two parts of the hippocampus, the perforant pathway and dentate gyrus, Lømo observed the electrical changes in the dentate gyrus elicited by stimulation of the perforant pathway. As expected, a single pulse of electrical stimulation to the perforant pathway elicited an excitatory postsynaptic potential (EPSP) in the dentate gyrus. What Lømo did not expect was that the postsynaptic responses to these single-pulse stimuli could be enhanced by first delivering a high-frequency train of stimuli to the synapse. When such a train of stimuli was applied, subsequent single-pulse stimuli elicited stronger, prolonged EPSPs. This phenomenon, whereby a high-frequency stimulus could enhance the postsynaptic cell's response to subsequent single-pulse stimuli, was soon dubbed "long-term potentiation".

Timothy Bliss, who joined the Andersen laboratory in 1968, collaborated with Lømo in 1973 to publish the first characterization of LTP in rabbit hippocampus.[5]

[edit] Types

Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the cerebral cortex, cerebellum, amygdala, and many others. Robert Malenka, a prominent LTP researcher, has suggested that LTP may even occur at all excitatory synapses in the mammalian brain.[6]

The specific type of LTP exhibited between neurons depends on a number of factors. One such factor is the anatomic location where LTP is observed. For instance, LTP in the Schaffer collateral pathway of the hippocampus is very different than the LTP of the mossy fiber pathway. Another 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 mechanisms that underlie LTP of the adult hippocampus.[7] The complement of signaling pathways expressed by a particular cell also contributes to the specific type of LTP present. For example, some types of hippocampal LTP depend on the NMDA receptor, while others depend upon the metabotropic glutamate receptor (mGluR).[6]

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,[6] and is therefore the focus of this article.

[edit] Properties

NMDA receptor-dependent LTP classically exhibits four main properties: rapid induction, cooperativity, associativity, and input specificity.

Rapid induction
LTP can be rapidly induced by applying one or more brief tetanic stimuli to a presynaptic cell. (A tetanic stimulus is a high-frequency sequence of individual stimulation.)
Cooperativity
LTP can be induced either by strong tetanic stimulation of a single pathway to a synapse, or cooperatively via the weaker stimulation of many. It is explained by the presence of a stimulus threshold that must be reached in order to induce LTP.
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 the postsynaptic membrane, the individual postsynaptic depolarizations generated may collectively depolarize the postsynaptic cell enough to induce LTP cooperatively.
Associativity
Associativity 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. There is some evidence that associativity and cooperativity share the same underlying cellular mechanism (see Synaptic tagging).
Input specificity
Once induced, LTP at one synapse is not arbitrarily propagated to adjacent synapses; rather LTP is input specific. Long-term potentiation is only propagated to those synapses according to the rules of associativity and cooperativity.

[edit] Mechanism

Long-term potentiation occurs through a variety of mechanisms throughout the nervous system; no single mechanism unites all of LTP's many types. However, for the purposes of study, LTP is commonly divided into two events: induction and expression. Induction is the process by which a signal triggers the events of LTP to begin, while expression entails the responses to these inductive signals.

The precise mechanisms by which each type of LTP is induced and expressed are not known with complete certainty. The prototypical type of LTP, NMDA receptor-dependent LTP of the adult CA1 hippocampus, has received the majority of investigators' attention, and its molecular underpinnings are the most well established.

[edit] Induction

Main article: LTP induction

NMDA receptor-dependent LTP can be induced experimentally by applying a few trains of high-frequency (that is, tetanic) stimulation to the connection between two neurons.[8] An understanding of normal synaptic transmission illustrates how tetanic stimulation can induce LTP.

Through normal synaptic transmission, non-tetanic stimulation causes the release of the neurotransmitter glutamate from the presynaptic terminal onto the postsynaptic cell membrane, where it binds to AMPA receptors (AMPARs) embedded in the postsynaptic membrane. AMPA receptors are the main excitatory receptors in the brain, and are responsible for most of its moment-to-moment excitatory activity.[citation needed]. Glutamate binding to the AMPA receptor triggers the influx of predominantly sodium ions into the postsynaptic cell, causing a depolarization called the excitatory postsynaptic potential (EPSP).

The magnitude of the depolarization determines whether LTP will be induced in the postsynaptic cell. While a single presentation of the stimulus is not sufficient to induce LTP, repeated presentations given at high frequency cause the postsynaptic cell to be progressively depolarized as a result of EPSP summation. If each successive stimulus within a tetanic train reaches the postsynaptic cell before the previous EPSP can decay, successive EPSPs will add to the depolarization caused by the previous EPSPs. In synapses that exhibit NMDAR-dependent LTP, this progressive depolarization ultimately recruits NMDA receptors (NMDARs), receptors that allow a rapid influx of calcium when activated. While NMDARs are present at most postsynaptic membranes, at resting membrane potentials they are blocked by a magnesium ion that prevents the entry of calcium into the postsynaptic cell. Progressive depolarization through the summation of EPSPs relieves the magnesium blockade of the NMDAR, promoting calcium influx. The rapid rise in intracellular calcium concentration triggers the expression of LTP, specifically its early phase.

[edit] Expression

The expression of LTP is often divided into two phases: an early, protein synthesis-independent phase (E-LTP) that lasts between one and five hours, and a late, protein synthesis-dependent phase (L-LTP) that lasts from days to months.[9] Broadly, E-LTP produces a potentiation of a few hours duration. Some researchers believe that it does so by making the postsynaptic side of the synapse more sensitive to glutamate by inserting existing AMPA receptors into the postsynaptic membrane. Another theory proposes that E-LTP is the result of increased release of glutamate from the presynaptic terminal. Many researchers believe that LTP is due to both pre- and postsynaptic mechanisms.

The late phase of LTP results in a pronounced strengthening of the postsynaptic response largely through the synthesis of new proteins and the remodeling of synapses. These proteins include transcription factors (eg, CREB), glutamate receptors (eg, AMPA receptors), and structural proteins that enhance existing synapses and form new connections.

[edit] Early phase

Ca2+/calmodulin-dependent protein kinase II (CaMKII) appears to be an important mediator of the early, protein synthesis-independent phase of LTP.
Ca2+/calmodulin-dependent protein kinase II (CaMKII) appears to be an important mediator of the early, protein synthesis-independent phase of LTP.

Early LTP is the series of events that take place within minutes and hours following LTP induction. Few downstream molecular events leading to the expression and maintenance of E-LTP are known with certainty. Yet there is considerable evidence that E-LTP depends upon the activity of several protein kinases, including calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC),[10] protein kinase A (PKA),[11] mitogen-activated protein kinase (MAPK),[12][13] and tyrosine kinases.[14]

CaMKII and other protein kinases carry out the expression of E-LTP postsynaptically via two major mechanisms.[6] First, they chemically modify postsynaptic AMPA receptors by adding phosphate groups to them. Second, they mediate or modulate the insertion of AMPA receptors into the postsynaptic membrane. AMPA receptors are the brain's most abundant glutamate receptors and mediate the majority of its excitatory activity. By increasing the number of AMPA receptors at the synapse, future excitatory stimuli generate larger postsynaptic effects. Importantly, the delivery of AMPA receptors to the synapse during LTP is independent of protein synthesis. 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.[15]

While E-LTP is induced and expressed postsynaptically, an additional component of expression may occur presynaptically.[16] One hypothesis of presynaptic facilitation is that enhanced CaMKII activity during early LTP may give rise to CaMKII autophosphorylation and constitutive activation. Persistent CaMKII activity may promote the synthesis of a retrograde messenger that travels across the synaptic cleft to the presynaptic cell, leading to a chain of events that facilitate the presynaptic response to subsequent stimuli. (See Retrograde signaling for discussion of the identity of the retrograde messenger.)

[edit] Late phase

The late phase of LTP is dependent upon gene expression and protein synthesis, regulated largely by CREB-1.
The late phase of LTP is dependent upon gene expression and protein synthesis, regulated largely by CREB-1.

Late LTP is the natural extension of E-LTP. There is controversy over whether L-LTP can be induced separately from E-LTP, so that possibility will not be considered here. Unlike early LTP, late LTP requires gene transcription[17][18] and protein synthesis,[19] helping to make LTP an attractive candidate for the molecular analog of long-term memory.

The synthesis of gene products is driven by kinases which in turn activate transcription factors that mediate gene expression. cAMP response element binding protein-1 (CREB-1) is thought to be the primary transcription factor in the cascade of gene expression that leads to prolonged structural changes to the synapse enhancing its strength.[20] CREB-1 is both necessary[21] and sufficient[22] for late LTP. It is active in its phosphorylated form and induces the transcription of immediate-early genes, including c-fos and c-jun.[23] Ultimately, the products of CREB-1-mediated transcription and protein synthesis give rise to new building materials for the synaptic connection between pre- and postsynaptic cell.

During L-LTP, constitutively active CaMKII activates a related kinase, CaMKIV. Additionally, enhanced Ca2+ levels during late LTP increase cAMP synthesis via adenylyl cyclase-1, further activating PKA and resulting in the phosphorylation and activation of MAPK.[24] Facilitated by cAMP, both CaMKII and CaMKIV translocate to the cell nucleus along with PKA and MAPK (mediated by PKA),[25] where they phosphorylate CREB-1.[26]

There is also some evidence that L-LTP is mediated in part by nitric oxide (NO).[27] In particular, NO may activate guanylyl cyclase, leading to the production of cyclic GMP and activation protein kinase G (PKG), which phosphorylates CREB-1. PKG may also cause the release of Ca2+ from ryanodine receptor-gated intracellular stores, increasing the Ca2+ concentration which activates other previously mentioned kinase cascades to further activate CREB-1.

[edit] Retrograde signaling

Retrograde signaling is a hypothesis that attempts to explain that, while LTP is induced and expressed postsynaptically, some evidence suggests the presence of a presynaptic component of expression.[6][28][29] The hypothesis gets its name because normal synaptic transmission is directional and proceeds from the presynaptic to the postsynaptic cell in an anterograde direction. For induction to occur postsynaptically and be partially expressed presynaptically, a message must travel from the postsynaptic cell to the presynaptic cell in a retrograde direction. Retrograde signaling is currently a contentious subject as some investigators do not believe the presynaptic cell contributes at all to the expression of LTP.[6]

Among supporters of the hypothesis, there is disagreement over the identity of the messenger. A flurry of work in the early 1990s to demonstrate the existence of a retrograde messenger and to determine its identity generated a list of candidates including carbon monoxide,[30] platelet-activating factor,[31][32] arachidonic acid, and nitric oxide. Nitric oxide has received a great deal of attention in the past, but has recently been superseded by adhesion proteins that span the synaptic cleft to join the presynaptic and postsynaptic cells.[6]

[edit] Synaptic tagging

The gene expression and protein synthesis that mediate the long-term changes of LTP generally take place in the cell body, but LTP is synapse-specific: LTP induced at one synapse does not propagate to adjacent inactive synapses. Therefore, the neuron is posed with the difficult problem of synthesizing plasticity-related proteins in the cell body, but ensuring they only reach synapses that have received LTP-inducing stimuli.

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.[33] Studies of LTP in the marine snail Aplysia californica have implicated synaptic tagging as a mechanism for the input-specificity of LTP.[34][35] 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 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.

The synaptic tag hypothesis may also account for LTP's associativity. Associativity (see Properties, above) 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), both synapses will in fact undergo LTP. While weak stimuli are unable to induce gene expression in the cell nucleus, they may prompt the synthesis of a synaptic tag. Simultaneous strong stimulation of a separate pathway, capable of inducing nuclear gene expression, then may prompt the production of 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.

Synaptic tagging may also explain LTP's cooperativity. While weak stimulation of a single pathway is insufficient to induce LTP, the simultaneous weak stimulation of two pathways is sufficient. According to the hypothesis, weak stimulation initiates the synthesis of a synaptic tag, but is insufficient to trigger late LTP and thus CREB-1-mediated gene expression. But simultaneous weak input converges on kinases that sufficiently activate CREB-1 thereby inducing the synthesis of plasticity-related proteins, which are shipped out cell-wide as described previously. Since a synaptic tag would have been synthesized at both synapses, both capture the products of gene expression and both are subsequently potentiated.

[edit] Modulation

LTP modulators[36]
Modulator Putative target
DA receptors cAMP, MAPK amplification
β-adrenergic receptors cAMP, MAPK amplification
mGluR PKC, MAPK amplification
NO synthase Guanylyl cyclase, PKG, NMDAR

In addition to the signalling pathways described above, hippocampal LTP can be modulated by a variety of molecules. For example, the steroid hormone estradiol is one of several molecules that enhances LTP by driving CREB-1 phosphorylation and subsequent dendritic spine growth.[37] Additionally, β-adrenergic receptor agonists such as norepinephrine contribute to the protein synthesis-dependent late phase of LTP.[38] Nitric oxide synthase also plays an important role, leading to the up-regulation of nitric oxide and subsequent activation of guanylyl cyclase and PKG, as described previously.[39] Similarly, activation of dopamine receptors enhances LTP via the cAMP/PKA signaling pathway.[40][41]

[edit] Relationship to behavioral memory

While long-term potentiation of cultured synapses 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 in vitro studies. For this reason, considerable effort has been dedicated to establishing whether LTP is a requirement for learning and memory in living animals.

[edit] Role in spatial memory

The Morris water maze task has been used to demonstrate the necessity of NMDA receptors in establishing spatial memories.
The Morris water maze task has been used to demonstrate the necessity of NMDA receptors in establishing spatial memories.

In 1986, Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories in vivo.[42] He tested the spatial memory of rats by pharmacologically modifying their hippocampus, a brain structure whose role in spatial learning is well established. One group of rats had their hippocampi bathed in the NMDA receptor blocker APV, while the other group was the control. Both groups were then subjected to the Morris water maze, in which rats were placed into a circular pool of murky water and tested on how quickly they could locate a platform hidden just beneath the water's surface. 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 some evidence that the NMDA receptor — and by extension, LTP — was somehow involved with at least some types of learning and memory.

Similarly, Susumu Tonegawa demonstrated in 1996 that the CA1 hippocampus is crucial to the formation of spatial memories in living mice.[43] So-called place cells located in this region fire when the rat is in a particular location in the environment. Since a large group of these cells will have place fields evenly distributed throughout the environment, one interpretation is that these cells form a sort of map. The accuracy of these maps determines how well a rat learns about its environment, and thus how well it can navigate about 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, rats produced faulty spatial maps when their NMDA receptors were impaired. As expected, these rats performed very poorly on spatial tasks compared to controls, providing more support to the notion that LTP is the underlying mechanism of spatial learning.

Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. In 2001, Joe Tsien produced a line of mice with enhanced NMDA receptor function by overexpressing the NR2B subunit in the hippocampus.[44] The resulting smart mice, nicknamed "Doogie mice" after the prodigious doctor Doogie Howser, had larger LTP and excelled at spatial learning tasks, once again suggesting a role for LTP in the formation of hippocampal-dependent memories.

[edit] Role in inhibitory avoidance

In 2006, Jonathan Whitlock and colleagues reported on a series of experiments that provided perhaps the strongest evidence of LTP's role in behavioral memory, arguing that in order to conclude that LTP underlies behavioral learning, the two processes must both mimic and occlude one another.[45] Employing an inhibitory avoidance learning 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 the same type of AMPA receptor phosphorylation seen in LTP in vitro. 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."[46]

[edit] Methods of experimental research

Since its discovery in hippocampal slices in 1966, long-term potentiation has remained an avidly studied topic in research laboratories worldwide. Some investigators have employed rudimentary PubMed searches in an attempt to quantify the extent to which LTP is studied.[6] As of February 2007, a PubMed search for the term "long-term potentiation or LTP" yields nearly 8000 publications.[47]

While this article is specific to NMDA receptor-dependent LTP in the CA1 hippocampus, there are many other types of LTP that occur throughout the nervous system, including the cerebral cortex, cerebellum, amygdala, and other subcortical structures. Indeed, LTP is not limited to the mammalian nervous system. A popular model of LTP study is the marine snail Aplysia californica, whose small nervous system of just a few thousand neurons is well suited for neurophysiological investigation. Using a reduced preparation of the animal, in which its nervous system is dissected out intact, researchers can study the snail's gill and siphon withdrawal reflex.

[edit] See also

[edit] References

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  20. ^ Poser S, Storm DR (2001). "Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation". Int J Dev Neurosci 19 (4): 387-94. PMID 11378299. 
  21. ^ Dash PK, Hochner B, Kandel ER (1990). "Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation". Nature 345 (6277): 718-21. PMID 2141668. 
  22. ^ Bartsch D, Casadio A, Karl KA, Serodio P, Kandel ER (1998). "CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation". Cell 95 (2): 211-23. PMID 9790528. 
  23. ^ Kasahara J, Fukunaga K, Miyamoto E (2001). "Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region". J Biol Chem 276 (26): 24044-50. PMID 11306573. 
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  28. ^ Cite error: Invalid <ref> tag; no text was provided for refs named emptage
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