Long-term potentiation
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In neuroscience, long-term potentiation (LTP) is an increase in the chemical strength of a synapse that lasts for more than an hour. This increase in synaptic strength moves the membrane potential closer to threshold, making it more likely that a subsequent stimulus will trigger an action potential.
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. Most neuroscientific learning theories regard long-term potentiation and its opposing process, long-term depression, as the cellular bases of learning and memory.
Experimentally, a series of short, high-frequency electric stimulations to a nerve cell synapse can strengthen, or potentiate, that synapse for minutes to hours. In living cells, LTP occurs naturally and can last from hours to days, months, and years.
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.
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[edit] History
[edit] Early theories of learning
By about 1900, neurobiologists had good reason to believe that memories were generally not the product of new nerve cell growth. Scientists generally believed that the number of neurons in the adult brain (roughly 1011) did not increase significantly with age. With this realization came the need to explain how memories were created in the absence of new cell growth.
Among the first neuroscientists to suggest that learning was not the product of new cell growth was the Spanish anatomist Santiago Ramón y Cajal. In 1894 he proposed that memories might be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. 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.[1]
However, these theories of memory formation were foresighted, as neuroscientists were not yet 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 observed by Terje Lømo in 1966 in the Oslo, Norway, laboratory of Per Andersen.[2] 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.[3]
[edit] Types of LTP
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.[4]
The specific type of LTP exhibited between neurons depends on a number of factors. One such factor is 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.[5] 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).[4]
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.[4]
[edit] Properties of LTP
NMDA receptor-dependent LTP classically exhibits four main properties: rapid induction, cooperativity, associativity, and input specificity.
[edit] 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.)
[edit] 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.
[edit] 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).
[edit] Input specificity
Once induced, LTP at one synapse is not propagated to adjacent synapses; rather LTP is input specific.
[edit] Phases of LTP
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.[6] 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 adding additional AMPA receptors into the postsynaptic membrane. Another theory proposes that E-LTP is the result of increased release of glutamate from the presynaptic terminal.
Conversely, L-LTP results in a pronounced strengthening of the postsynaptic response largely through the synthesis of new proteins. These proteins include glutamate receptors (e.g. AMPAR), transcription factors, and structural proteins that enhance existing synapses and form new connections. There is also considerable evidence that late LTP prompts the postsynaptic synthesis of a retrograde messenger that diffuses to the presynaptic cell increasing the probability of neurotransmitter vesicle release on subsequent stimuli. All of this is largely hypothetical. The proposed mechanism of L-LTP are only weakly supported by existing data. Many investigators in the field doubt the very existence of L-LTP.
[edit] Early LTP
E-LTP can be induced experimentally by applying a few trains of tetanic stimulation to the connection between two neurons.[7] Through normal synaptic transmission, this stimulation causes the release of neurotransmitters, particularly glutamate, from the presynaptic terminal onto the postsynaptic cell membrane, where they bind to neurotransmitter receptors embedded in the postsynaptic membrane. Though a single presentation of the stimulus is not sufficient to induce LTP, repeated presentations, if given at high-enough frequency, cause the postsynaptic cell to be progressively depolarized. This progressive depolarization is the 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 relieves the magnesium blockade of the NMDA receptor. When the magnesium block is removed, successive stimuli promote calcium entry through the NMDAR channel into the postsynaptic cell, rapidly increasing the intracellular concentration of calcium. It is this rapid rise in calcium concentration that induces E-LTP.
Beyond calcium's critical role in the induction of E-LTP, 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 induction depends upon the activity of several protein kinases, including calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC),[8][9] protein kinase A (PKA),[10] mitogen-activated protein kinase (MAPK),[11][12] and tyrosine kinases.[13]
Postsynaptically, the early phase of LTP is expressed primarily through the addition of new AMPA receptors to the postsynaptic membrane. In NMDA-dependent LTP in the CA1 hippocampus, the endogenous calcium chelator calmodulin rapidly binds calcium that is made available to it because it enters the cell through the NMDA receptor.[14] The calcium-calmodulin complex directly activates CaMKII which 1) phosphorylates voltage-gated potassium channels increasing their excitability;[15] 2) enhances the activity of existing AMPA receptors; and 3) phosphorylates intracellular AMPARs and activates Syn GAP (a Ras GTPase activating protein) and the MAPK cascade, facilitating the insertion of preexisting AMPARs into the postsynaptic membrane.[16]
PKA serves a role similar to that of CaMKII, but PKA's effects are more broad. PKA's activity is enhanced during LTP induction by elevated levels of cAMP as a result of calcium's activation of adenylyl cyclase-1. Like CaMKII, PKA phosphorylates voltage-dependent potassium channels and also calcium channels enhancing their excitability to future stimuli. Additionally, PKA phosphorylates intracellular AMPAR stores, facilitating their insertion postsynaptically. PKA may also enhance AMPAR delivery via activation of the MAPK cascade. However, the role of PKA, especially in early LTP is very controversial.
While LTP is induced postsynaptically, it is partially expressed presynaptically. One hypothesis of presynaptic facilitation is that enhanced CaMKII activity during early LTP gives rise to CaMKII autophosphorylation and constitutive activation. Persistent CaMKII activity then stimulates NO synthase, leading to the enhanced production of the putative retrograde messenger, NO. Since NO is a diffusable gas, it freely diffuses across the synaptic cleft to the presynaptic cell leading to a chain of molecular events that facilitate the presynaptic response to subsequent stimuli. (See Retrograde signaling for discussion about the identity of the retrograde messenger.)
[edit] Late LTP
Late LTP can be experimentally induced by a series of three or more trains of tetanic stimulation spaced roughly 10 minutes apart. Unlike early LTP, late LTP requires gene transcription[17][18] and protein synthesis,[19] making it 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 so-called 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 signalling is a theoretical concept that arises from the question: "If LTP is induced postsynaptically, but expressed presynaptically, how does the presynaptic terminal "know" that LTP has been induced?" The obvious answer is that there must be some communication "backwards" across the synapse, that is, in the retrograde direction from the postsynaptic to the presynaptic side. This concept led to a flurry of work in the early 1990's to demonstrate the existence of a retrograde messenger and also to identify such a messenger. A number of candidates were examined including carbon monoxide,[28] platelet-activating factor,[29][30] arachidonic acid, and nitric oxide.[31][32]
Perhaps unfortunately for the retrograde signaling hypothesis, subsequent work has strongly established that LTP, at least early LTP, is expressed entirely postsynaptically (cf. Malenka and Bear, 2004). However, there is still life in the retrograde signalling hypothesis, since it has been demonstrated that induction of LTP may involve a retrograde messenger, since contrary to dogma, LTP induction does not appear to be entirely postsynaptic.[33]
[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 cell is posed with the difficult problem of synthesizing plasticity-related proteins in the nucleus and cell body, but ensuring they only reach synapses that have received LTP-inducing stimuli.
The synthesis of a "synaptic tag" at a given synapse after LTP-inducing stimuli may serve to capture plasticity-related proteins shipped cell-wide from the nucleus.[34] Studies of LTP in the marine snail Aplysia californica have implicated synaptic tagging as a mechanism for the input-specificity of LTP.[35][36] 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 input receiving LTP-inducing stimuli is potentiated, demonstrating LTP's input-specificity.
The synaptic tag hypothesis may also give rise to LTP's associativity. Associativity (see 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 appear to prompt the synthesis of a synaptic tag. Simultaneous strong stimulation of a separate pathway, capable of inducing nuclear gene expression, then prompts the production of plasticity-related proteins, which are shipped cell-wide. With both synapses expressing the synaptic tag, both capture the protein products resulting in the induction 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] LTP modulation
| 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.[38] Additionally, β-adrenergic receptor agonists such as norepinephrine contribute to the protein synthesis-dependent late phase of LTP.[39] 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.[40] Similarly, activation of dopamine receptors enhances LTP via the cAMP/PKA signaling pathway.[41][42]
[edit] LTP and behavioral memory
The mere fact that cultured synapses can undergo long-term potentiation when stimulated by electrodes says little about LTP's relation to memory in an intact organism. Several studies have provided some insight as to whether LTP is a requirement for memory.
[edit] NMDAR blockade
Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories.[43] He tested the spatial memory of two groups of rats, one whose hippocampi were bathed in the NMDA receptor blocker APV, and the other acting as a control group. (The hippocampus, where LTP was originally observed, is required for some forms of spatial learning). Both groups were then subjected to the Morris water maze, in which rats were placed into a circular pool of murky water (often made opaque with milk powder or white paint) 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, whereas the ability of APV-treated rats to complete the task was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups of rats, 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 thus LTP — was somehow involved with at least some types of learning and memory.
Similarly, Susumu Tonegawa has demonstrated that a specific region of the hippocampus, namely CA1, is crucial to the formation of spatial memories.[44] 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 NMDAR1 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.
[edit] Doogie mice
Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. Joe Tsien produced a line of mice with enhanced NMDA receptor function by overexpressing its NR2B subunit in the hippocampus.[45] The resulting smart mice, nicknamed "Doogie mice" after the prodigious doctor Doogie Howser, had larger long-term potentiation and excelled at spatial learning tasks, once again suggesting LTP's involvement in the formation of hippocampal-dependent memories.
[edit] See also
[edit] References
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