Long-term potentiation is the persistent increase in synaptic strength following high-frequency stimulation of a synapse. Studies of long-term potentiation are often carried out in slices of the hippocampus, an organ of central importance in learning and memory. In such studies, cellular voltage recordings are made and plotted in a graph such as this one. This demonstrates the enhanced response to stimuli in synapses that have undergone LTP compared to the baseline response in synapses that have not undergone LTP.
In
neuroscience, 'long-term potentiation' ('LTP') is a persistent increase in the chemical strength of a
synapse that can last from minutes to several days after a single stimulus. Since memories are believed to be formed and stored within synapses of the brain, LTP is widely considered one of the major mechanisms by which the brain
learns and maintains
memories.
LTP has been observed both in experimental preparations ''in vitro'' and in living animals (''in vivo''). Under experimental conditions, applying a series of short, high-frequency electric stimuli to a synapse can strengthen, or ''potentiate'', the synapse for minutes to hours. In living animals, 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 one cell are more likely to elicit
action potentials in the cell to which it is connected.
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 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 learning and memory.
History
Early theories of learning
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 100 billion
[1]) did not increase significantly with age, giving neurobiologists good reason to believe that memories were generally not the result of new nerve cell production.
[2] 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 result of the creation of new cells through cell division 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.
, 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:
Though these theories of memory formation are now well established, they were farsighted 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.
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 illustration of the underside of the
human brain shows the hippocampus highlighted in red. The
frontal lobe is at the top of the illustration 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.
[3] 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 for a long period of time 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 produce a long-lived enhancement in the postsynaptic cell's response to subsequent single-pulse stimuli, was initially called "long-lasting potentiation".
[4][5]
Timothy Bliss, 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
rabbit 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 potentiation.
[6] Andersen has suggested that the authors proposed "long-term potentiation" for its easily pronounced acronym, "LTP".
[7]
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.
[8]
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 mechanisms that underlie LTP of the adult hippocampus.
[9] 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, others may depend upon the
metabotropic glutamate receptor (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 in part upon the anatomic location in which LTP is observed. For example, LTP in the
Schaffer collateral pathway of the hippocampus is NMDA receptor-dependent, whereas LTP in the
mossy fiber pathway is NMDA receptor-independent.
[10]
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.
Properties
NMDA receptor-dependent LTP classically exhibits four main properties: rapid induction, input specificity, associativity, and cooperativity.
; 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 electrical stimuli.)
; 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.
; 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.
; 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. 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 postsynaptic depolarizations generated may collectively depolarize the postsynaptic cell enough to induce LTP cooperatively. Associativity and cooperativity may share the same underlying cellular mechanism (''see
Synaptic tagging'').
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 three phases that occur sequentially: short-term potentiation, early LTP, and late LTP.
Little is known about the mechanisms of short-term potentiation,
so it will not be discussed here.
Each phase of LTP is governed by a set of mediators, small molecules that dictate the events of that phase.
These molecules include
protein receptors that respond to events outside of the cell,
enzymes that carry out
chemical reactions within the cell, and
signaling molecules that allow the progression from one phase to the next. In addition to these mediators, there are also modulator molecules that interact with mediators to finely alter the LTP ultimately generated. (''See
Modulation for details.'')
The early (E-LTP) and late (L-LTP) phases of LTP are each characterized by a series of three events: induction, maintenance, and expression. ''Induction'' is the process by which a short-lived signal triggers that phase of LTP to begin. ''Maintenance'' corresponds to the persistent biochemical changes that occur in response to the induction of that phase. Finally, ''expression'' entails the long-lasting cellular changes that result from activation of the maintenance signal.
Thus the mechanisms of LTP can be discussed in terms of those that underlie the induction, maintenance, and expression of E-LTP and L-LTP.
Early LTP
The early phase of LTP, one model of which is shown here, is independent of protein synthesis.
Ca2+/calmodulin-dependent protein kinase II (CaMKII) appears to be an important mediator of the early, protein synthesis-independent phase of LTP.
Induction
Main articles: LTP induction
Induction of E-LTP occurs when the concentration of
calcium inside the postsynaptic cell exceeds a critical threshold.
[11] In many types of LTP, the flow of calcium into the cell requires the
NMDA receptor, which is why these types of LTP are considered to be NMDA receptor-dependent.
NMDA receptor-dependent LTP can be induced experimentally by applying a few trains of high-frequency stimuli to the connection between two neurons.
[12] An understanding of normal synaptic transmission illustrates how this
tetanic stimulation can induce E-LTP.
Chemical synapses are functional connections between
neurons throughout the nervous system. In a typical synapse, information is passed from the first (presynaptic) neuron to the second (postsynaptic) neuron via a process of
synaptic transmission. Through experimental manipulation, a non-tetanic stimulus can be applied to the presynaptic cell, causing it to release a
neurotransmitter—typically
glutamate—onto the postsynaptic cell membrane. There, glutamate binds to
AMPA receptors (AMPARs) embedded in the postsynaptic membrane. The AMPA receptor is one of the main excitatory receptors in the brain, and is responsible for most of its rapid, moment-to-moment excitatory activity.
[13] Glutamate binding to the AMPA receptor triggers the influx of predominantly
sodium ions into the postsynaptic cell, causing a short-lived depolarization called the
excitatory postsynaptic potential (EPSP).
The magnitude of this depolarization determines whether E-LTP will be induced in the postsynaptic cell. While a single stimulus does not generate an EPSP capable of inducing E-LTP, repeated stimuli given at high frequency cause the postsynaptic cell to be progressively depolarized as a result of
EPSP summation: with each EPSP reaching the postsynaptic cell before the previous EPSP can decay, successive EPSPs add to the depolarization caused by the previous EPSPs. In synapses that exhibit NMDA receptor-dependent LTP, sufficient depolarization unblocks
NMDA receptors (NMDARs), receptors that allow
calcium to flow into the cell when bound by glutamate. 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. Sufficient depolarization through the summation of EPSPs relieves the magnesium blockade of the NMDAR, allowing calcium influx. The rapid rise in intracellular calcium concentration triggers the short-lasting activation of several enzymes that mediate E-LTP induction. Of particular importance are some
protein kinase enzymes, including
calcium/calmodulin-dependent protein kinase II (CaMKII) and
protein kinase C (PKC).
To a lesser extent,
protein kinase A (PKA) and
mitogen-activated protein kinase (MAPK) activation also contribute to the induction of E-LTP.
Maintenance
While induction entails the ''transient'' activation of CaMKII and PKC, maintenance of E-LTP is characterized by their ''persistent'' activation. During this stage, CaMKII and PKC lose their dependence on calcium and become autonomously active. Consequently they are able to carry out the phosphorylation events that underlie E-LTP expression.
Expression
Phosphorylation is a chemical reaction in which a small
phosphate group is added to another molecule in order 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
AMPA receptors 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
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.
[14] 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.
While the above model of E-LTP describes entirely postsynaptic mechanisms for induction, maintenance, and expression, an additional component of expression may occur presynaptically.
[15] One hypothesis of this presynaptic facilitation is that persistent CaMKII activity during E-LTP may lead to the synthesis of a "retrograde messenger". 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 early LTP, the retrograde messenger may also play a role in the expression of late LTP. (''See
Retrograde signaling for further discussion.'')
Late LTP
Late LTP is the natural extension of E-LTP. Unlike E-LTP, which is independent of protein synthesis, L-LTP requires
gene transcription[16] and
protein synthesis[17] 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.
Induction
There is controversy over whether L-LTP can be induced separately from E-LTP, so that possibility will not be considered here. Rather, L-LTP is induced by changes in
gene expression and
protein synthesis brought about by the persistent activation of protein kinases activated during E-LTP, such as MAPK.
In fact, MAPK—specifically the
extracellular signal-regulated kinase (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, can converge on ERK.
Maintenance
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
transcription factors such as
cAMP response element binding protein (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
protein kinase Mζ (PKMζ), a persistently active kinase whose synthesis increases following LTP induction.
[18][19] 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
long-term memory. Indeed, administration of a PKMζ inhibitor into the hippocampi of rats results in
retrograde amnesia with intact
short-term memory; 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.
Expression
Aside from PKMζ, 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
dendritic spine 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
synaptotagmin and an increase in
synaptic vesicle number, suggesting that L-LTP induces protein synthesis not only in postsynaptic cells, but in presynaptic cells as well.
As mentioned previously, in order for postsynaptic LTP induction to result in presynaptic protein synthesis, there must be communication from the postsynaptic to the presynaptic cell. (''See
Retrograde signaling.'')
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
cell body or in its
dendrites.
[20] Despite having observed
ribosomes (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 dogma 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.
[21][22]
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 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, see
Synaptic tagging for a model that reconciles global protein synthesis, synapse specificity, and associativity.'')
Retrograde signaling
Main articles: Retrograde signaling in LTP
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
synaptic transmission 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 ''retrograde'' (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
neurotransmitter vesicle release.
[24]
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
nitric oxide, while most recent evidence points to
cell adhesion proteins.
Synaptic tagging
Before the local protein synthesis hypothesis (''see
Late LTP'') 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 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.
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.
[25] Studies of LTP in the
marine snail ''
Aplysia californica'' have implicated synaptic tagging as a mechanism for the input-specificity of LTP.
[26][27] 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 and cooperativity. Associativity (''see
Properties'') 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 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 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.
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 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.
Modulation
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 that can alter LTP but is not essential for its generation or expression.
In addition to the signaling pathways described above, hippocampal LTP may be altered by a variety of modulators. For example, the
steroid hormone estradiol may enhance LTP by driving CREB phosphorylation and subsequent
dendritic spine growth.
[29] Additionally,
β-adrenergic receptor agonists such as
norepinephrine may alter the protein synthesis-dependent late phase of LTP.
[30] Nitric oxide synthase activity may also result in the subsequent activation of guanylyl cyclase and PKG.
[31] Similarly, activation of
dopamine receptors may enhance LTP through the cAMP/PKA signaling pathway.
[32][33]
Relationship to behavioral memory
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 ''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.
Role in spatial memory
In 1986, Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories ''in vivo''.
[34] He tested the
spatial memory of rats by pharmacologically modifying their hippocampus, a brain structure whose role in spatial learning is well established. Rats were pretrained on the
Morris water maze, 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. Following pretraining, one group of rats had their hippocampi bathed in the NMDA receptor blocker
APV, while the other group served as the
control. Both groups were then subjected again 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 some early 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 area of the hippocampus is crucial to the formation of spatial memories in living mice.
[35] So-called ''
place cells'' located in this region become active only when the rat is in a particular location — called a ''place field'' — 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, 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.
[36] 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 hippocampus-dependent memories.
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.
[37] 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 ''in vivo'' AMPA receptor phosphorylation of the same type as that seen in LTP ''in vitro''; 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."
[38]
See also
★
Synaptic plasticity
★
Neuroplasticity
★
Long-term depression
★
Long-term memory
★
Learning
★
Memory
References
1. The control of neuron number, Williams RW, Herrup K, , , Annu. Rev. Neurosci., 1988
2. The Croonian Lecture: La Fine Structure des Centres Nerveux, Ramón y Cajal, Santiago, , , Proceedings of the Royal Society of London, 1894
3. The discovery of long-term potentiation, Terje Lømo, , , Philos Trans R Soc Lond B Biol Sci, 2003
4. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path, Bliss T, Lømo T, , , J Physiol, 1973
5. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path, Bliss T, Gardner-Medwin A, , , J. Physiol. (Lond.), 1973
6. Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus, Douglas R, Goddard G, , , Brain Res., 1975
7. A prelude to long-term potentiation, Andersen P, , , Philos. Trans. R. Soc. Lond., B, Biol. Sci., 2003
8. LTP and LTD: an embarrassment of riches, Malenka R, Bear M, , , Neuron, 2004
9. A developmental switch in the signaling cascades for LTP induction, Yasuda H, Barth A, Stellwagen D, Malenka R, , , Nat Neurosci, 2003
10. Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists, Harris E, Cotman C, , , Neurosci Lett, 1986
11. Long-term potentiation and memory, Lynch M, , , Physiol Rev, 2004
12. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization, Huang Y, Kandel E, , , Learn Mem, 1994
13. Basic neurochemistry: molecular, cellular, and medical aspects, Agranoff, Bernard W.; Siegel, George J., , , Lippincott-Raven, 1999,
14. AMPA receptor trafficking and long-term potentiation, Malinow R, , , Philos Trans R Soc Lond B Biol Sci, 2003
15. Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses, Emptage N, Reid C, Fine A, Bliss T, , , Neuron, 2003
16. Influence of actinomycin D, a RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro, Frey U, Frey S, Schollmeier F, Krug M, , , J Physiol, 1996
17. Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro, Frey U, Krug M, Reymann K, Matthies H, , , Brain Res, 1988
18. Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation, Serrano P, Yao Y, Sacktor T, , , J Neurosci, 2005
19. Storage of spatial information by the maintenance mechanism of LTP, Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton A, Sacktor T, , , Science, 2006
20. Translational regulatory mechanisms in persistent forms of synaptic plasticity, Kelleher R, Govindarajan A, Tonegawa S, , , Neuron, 2004
21. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity, Kang H, Schuman E, , , Science, 1996
22. A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites, Steward O, Worley P, , , Proc Natl Acad Sci U S A, 2001
23. Presynaptic protein kinase activity supports long-term potentiation at synapses between individual hippocampal neurons, Pavlidis P, Montgomery J, Madison D, , , J Neurosci, 2000
24. Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses, Zakharenko S, Patterson S, Dragatsis I, Zeitlin S, Siegelbaum S, Kandel E, Morozov A, , , Neuron, 2003
25. Synaptic tagging and long-term potentiation, Frey U, Morris R, , , Nature, 1997
26. Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage, Martin K, Casadio A, Zhu H, Yaping E, Rose J, Chen M, Bailey C, Kandel E, , , Cell, 1997
27. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis, Casadio A, Martin K, Giustetto M, Zhu H, Chen M, Bartsch D, Bailey C, Kandel E, , , Cell, 1999
28. Toward a molecular explanation for long-term potentiation, Sweatt J, , , Learn Mem, 1999
29. CREB activation mediates plasticity in cultured hippocampal neurons, Segal M, Murphy D, , , Neural Plast, 1999
30. 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, Straube T, Frey J, , , Neuroscience, 2003
31. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus, Lu Y, Kandel E, Hawkins R, , , J Neurosci, 1999
32. The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro, Frey U, Matthies H, Reymann K, Matthies H, , , Neurosci Lett, 1991
33. D1/D5 dopamine receptor activation increases the magnitude of early long-term potentiation at CA1 hippocampal synapses, Otmakhova N, Lisman J, , , J Neurosci, 1996
34. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5, Morris R, Anderson E, Lynch G, Baudry M, , , Nature, 1986
35. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice, McHugh T, Blum K, Tsien J, Tonegawa S, Wilson M, , , Cell, 1996
36. Differential effects of enrichment on learning and memory function in NR2B transgenic mice, Tang Y, Wang H, Feng R, Kyin M, Tsien J, , , Neuropharmacology, 2001
37. Learning induces long-term potentiation in the hippocampus, Whitlock J, Heynen A, Shuler M, Bear M, , , Science, 2006
38. Neuroscience. ZAP and ZIP, a story to forget, Bliss T, Collingridge G, Laroche S, , , Science, 2006
External links
★
Researchers provide first evidence for learning mechanism, a
PhysOrg.com report on 2006 study by Bear and colleagues.
★
Scientific American article about the Doogie mice.
★
Short video documentary about the Doogie mice. (
RealPlayer format)
★
"Smart Mouse", a Quantum ABC TV episode about the Doogie mice.
★
العربية
中国
Français
Deutsch
Ελληνική
हिन्दी
Italiano
日本語
Português
Русский
Español
