Long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons.[2] The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.
It is one of several phenomena underlying
LTP was discovered in the rabbit hippocampus by Terje Lømo 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 learning and memory. LTP is also a subject of clinical research, for example, in the areas of Alzheimer's disease and addiction medicine.
History
Early theories of learning
At the end of the 19th century, scientists generally recognized that the number of neurons in the adult brain (roughly 100 billion[4]) did not increase significantly with age, giving neurobiologists good reason to believe that memories were generally not the result of new neuron production.[5] With this realization came the need to explain how memories could form in the absence of new neurons.
The
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.[7]
Eric Kandel (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.[8][9]
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 neurophysiological 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.
Discovery
LTP was first observed by Terje Lømo in 1966 in the Oslo, Norway, laboratory of Per Andersen.[10][11] There, Lømo conducted a series of neurophysiological experiments on anesthetized rabbits to explore the role of the hippocampus in short-term memory.
Lømo's experiments focused on connections, or synapses, from the
Timothy Bliss, who joined the Andersen laboratory in 1968,[10] collaborated with Lømo and in 1973 the two published the first characterization of long-lasting potentiation in the rabbit hippocampus.[12] 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.[13] In 1975, Douglas and Goddard proposed "long-term potentiation" as a new name for the phenomenon of long-lasting potentiation.[14][15] Andersen suggested that the authors chose "long-term potentiation" perhaps because of its easily pronounced acronym, "LTP".[16]
Models and theory
The physical and biological mechanism of LTP is still not understood, but some successful models have been developed.[1] Studies of
Types
Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the cerebral cortex,[18] cerebellum,[19] amygdala,[20] and many others. Robert Malenka, a prominent LTP researcher, has suggested that LTP may even occur at all excitatory synapses in the mammalian brain.[21]
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 mechanisms that underlie LTP of the adult hippocampus.[22] 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 NMDA receptor, others may depend upon the metabotropic glutamate receptor (mGluR), while still others depend upon another molecule altogether.[21] 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 Schaffer collateral pathway of the hippocampus is NMDA receptor-dependent - this was proved by the application of AP5, an antagonist to the NMDA receptor, which prevented LTP in this pathway.[23] Conversely, LTP in the mossy fiber pathway is NMDA receptor-independent, even though both pathways are in the hippocampus.[24]
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
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,[21] and is therefore, the focus of this article.
Properties
NMDA receptor-dependent LTP exhibits several properties, including input specificity, associativity, cooperativity, and persistence.
- Input specificity
- Once induced, LTP at one synapse does not spread to other synapses; rather LTP is input specific. 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.[citation needed] One model to explain the input specificity of LTP was presented by Frey and Morris in 1997 and is called the synaptic tagging and capture hypothesis.[28]
- 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.[29]
- 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. Synaptic tagging, discussed later, may be a common mechanism underlying associativity and cooperativity. Bruce McNaughton argues that any difference between associativity and cooperativity is strictly semantic.[30] Experiments performed by stimulating an array of individual dendritic spines, have shown that synaptic cooperativity by as few as two adjacent dendritic spines prevents long term depression (LTD) allowing only LTP.[31]
- Persistence
- LTP is persistent, lasting from several minutes to many months, and it is this persistence that separates LTP from other forms of synaptic plasticity.[32]
Early phase
Maintenance
While induction entails the transient activation of
Expression
Phosphorylation is a chemical reaction in which a small phosphate 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 AMPA receptors to increase their activity.[21] Second, they mediate or modulate the insertion of additional AMPA receptors into the postsynaptic membrane.[21] 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.[35] 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.[36] One hypothesis of this presynaptic facilitation is that persistent CaMKII activity in the postsynaptic cell during 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 early LTP, the retrograde messenger may also play a role in the expression of late LTP.
Late phase
Late LTP (L-LTP) is the natural extension of E-LTP. Unlike E-LTP, which is independent of protein synthesis, L-LTP requires
Induction
Late LTP is induced by changes in
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.
The long-term stabilization of synaptic changes is also determined by a parallel increase of pre- and postsynaptic structures such as
On the molecular level, an increase of the postsynaptic scaffolding proteinsExpression
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.[33] The latter may be brought about in part by the enhanced synthesis of AMPA receptors during L-LTP.[33] 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.[33] 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 may occur via the synthesis of a retrograde messenger, discussed later.
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
One reason for the popularity of the local protein synthesis hypothesis is that it provides a possible mechanism for the specificity associated with LTP.[39] 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, as discussed later, the synaptic tagging hypothesis successfully reconciles global protein synthesis, synapse specificity, and associativity.
Retrograde signaling
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.
Retrograde signaling is currently a contentious subject as some investigators do not believe the presynaptic cell contributes at all to the expression of LTP.[21] 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.[21]
Synaptic tagging
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 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. 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
Modulator | Target |
---|---|
β-Adrenergic receptor | cAMP, MAPK amplification |
Nitric oxide synthase | Guanylyl cyclase, PKG, NMDAR |
Dopamine receptor | cAMP, MAPK amplification |
Metabotropic glutamate receptor | PKC, MAPK amplification |
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.[21]
In addition to the signaling pathways described above, hippocampal LTP may be altered by a variety of modulators. For example, the
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. Because of this, LTP also plays a crucial role in fear processing.
Spatial memory
In 1986, Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories in vivo.
Similarly, Susumu Tonegawa demonstrated in 1996 that the CA1 area of the hippocampus is crucial to the formation of spatial memories in living mice.[58] 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, 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.
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 et al. produced a line of mice with enhanced NMDA receptor function by overexpressing the
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 to conclude that LTP underlies behavioral learning, the two processes must both mimic and occlude one another.[61] 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."[62]
Clinical significance
The role of LTP in disease is less clear than its role in basic mechanisms of
Alzheimer's disease
LTP has received much attention among those who study
In a 2003 review of the literature, Rowan et al. proposed one model for how LTP might be affected in AD.
AD may also impair LTP through mechanisms distinct from Aβ. For example, one study demonstrated that the enzyme PKMζ accumulates in neurofibrillary tangles, which are a pathologic marker of AD. PKMζ is an enzyme with critical importance in the maintenance of late LTP.[65]
Drug addiction
Research in the field of
See also
- Neuroplasticity
- Actin remodeling of neurons
- Transcranial direct-current stimulation
- Post-tetanic potentiation
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Further reading
- Bliss T, Collingridge G, Morris R (2004). Long-term potentiation: enhancing neuroscience for 30 years. Oxford: Oxford University Press. ISBN 978-0-19-853030-5.
- Andersen P, Morris R, Amaral D, Bliss T, O'Keefe J (2007). The hippocampus book. Oxford: Oxford University Press. pp. 350–474. ISBN 978-0-19-510027-3.
External links
- Researchers provide first evidence for learning mechanism, a PhysOrg.comreport on 2006 study by Bear and colleagues.
- Short video documentary about the Doogie mice. (RealPlayer format)
- "Smart Mouse", a Quantum ABC TV episode about the Doogie mice.
- Long-Term+Potentiation at the U.S. National Library of Medicine Medical Subject Headings (MeSH)