Жүйке байланыстарының белсенділігіне байланысты ұзақ мерзімді күшеюі

Persistent strengthening of synapses based on recent patterns of activity

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. The opposite of LTP is long term depression, which produces a long lasting decrease in synaptic strength. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength. As memories are thought to be encoded by modification of synaptic strength, LTP is widely considered one of the major cellular mechanisms that underlies learning and memory.) did not increase significantly with age, giving neurobiologists good reason to believe that memories were generally not the result of new neuron production. With this realization came the need to explain how memories could form in the absence of new neurons. The Spanish neuroanatomist Santiago Ramón y Cajal was among the first to suggest a mechanism of learning that did not require the formation of new neurons. In his 1894 Croonian Lecture, he proposed that memories might instead be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. 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. 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.

LTP was first observed by Terje Lømo in 1966 in the Oslo, Norway, laboratory of Per Andersen. 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 perforant pathway to the dentate gyrus. These experiments were carried out by stimulating presynaptic fibers of the perforant pathway and recording responses from a collection of postsynaptic cells of the dentate gyrus. As expected, a single pulse of electrical stimulation to fibers of the perforant pathway caused excitatory postsynaptic potentials (EPSPs) in cells of the dentate gyrus. What Lømo unexpectedly observed was that the postsynaptic cells' response to these single pulse stimuli could be enhanced for a long period of time if he first delivered a high frequency train of stimuli to the presynaptic fibers. When such a train of stimuli was applied, subsequent single pulse stimuli elicited stronger, prolonged EPSPs in the postsynaptic cell population. This phenomenon, whereby a high frequency stimulus could produce a long lived enhancement in the postsynaptic cells' response to subsequent single pulse stimuli, was initially called "long lasting potentiation". Timothy Bliss, who joined the Andersen laboratory in 1968, Andersen suggested that the authors chose "long term potentiation" perhaps because of its easily pronounced acronym, "LTP".

The physical and biological mechanism of LTP is still not understood, but some successful models have been developed. Studies of dendritic spines, protruding structures on dendrites that physically grow and retract over the course of minutes or hours, have suggested a relationship between the electrical resistance of the spine and the effective synapse strength, due to their relationship with intracellular calcium transients. Mathematical models such as BCM Theory, which depends also on intracellular calcium in relation to NMDA receptor voltage gates, have been developed since the 1980s and modify the traditional a priori Hebbian learning model with both biological and experimental justification. Still, others have proposed re arranging or synchronizing the relationship between receptor regulation, LTP, and synaptic strength.

While induction entails the transient activation of CaMKII and PKC, maintenance of E LTP (early form LTP) is characterized by their persistent activation. During this stage, PKMz (Protein kinase Mζ) which does not have dependence on calcium, become autonomously active. Consequently, they are able to carry out the phosphorylation events that underlie E LTP expression. 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. 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.

[[Image:Late LTP mechanism. png|right|thumb|200px|The early and late phases of LTP are thought to communicate via the extracellular signal regulated kinase (ERK). and protein synthesis 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. This requirement for a molecular coincidence accounts perfectly for the associative nature of LTP, and, presumably, for that of learning.

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.

thumb|250px|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. 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 trained 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. After training, 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 to the water maze spatial memory task. Rats in the control group were able to locate the platform and escape from the pool, while the performance of APV treated rats was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups, LTP was easily induced in controls, but could not be induced in the brains of APV treated rats. This provided early evidence that the NMDA receptor — and by extension, LTP — was required for at least some types of learning and memory. Similarly, Susumu Tonegawa demonstrated in 1996 that the CA1 area of the hippocampus is crucial to the formation of spatial memories in living mice. 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 NR2B subunit in the hippocampus. The resulting smart mice, nicknamed "Doogie mice" after the fictional prodigious doctor Doogie Howser, had larger LTP and excelled at spatial learning tasks, reinforcing LTP's importance in the formation of hippocampus dependent memories.

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. 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."

The role of LTP in disease is less clear than its role in basic mechanisms of synaptic plasticity. However, alterations in LTP may contribute to a number of neurological diseases, including depression, Parkinson's disease, epilepsy, and neuropathic pain. Impaired LTP may also have a role in Alzheimer's disease and drug addiction.

[[Image:APP and LTP in Alzheimer disease. png|thumb|150px|Misprocessing of amyloid precursor protein (APP) in Alzheimer's disease disrupts LTP and is thought to lead to early cognitive decline in individuals with the disease. AD appears to result, at least in part, from misprocessing of amyloid precursor protein (APP). The result of this abnormal processing is the accumulation of fragments of this protein, called amyloid β (Aβ). Aβ exists in both soluble and fibrillar forms. Misprocessing of APP results in the accumulation of soluble Aβ that, according to Rowan's hypothesis, impairs hippocampal LTP and may lead to the cognitive decline seen early in AD. 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.

Research in the field of addiction medicine has also recently turned its focus to LTP, owing to the hypothesis that drug addiction represents a powerful form of learning and memory. Addiction is a complex neurobehavioral phenomenon involving various parts of the brain, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc). Studies have demonstrated that VTA and NAc synapses are capable of undergoing LTP