Long-term potentiation Totally Explained

Everything about Long-term Potentiation totally explained

In neuroscience, long-term potentiation (LTP) is the long-lasting enhancement in communication between two neurons that results from stimulating them simultaneously. Since neurons communicate via chemical synapses, and because memories are believed to be stored within these synapses, LTP and its opposing process, long-term depression, are widely considered the major cellular mechanisms that underlie learning and memory.) didn't 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 didn't 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.}}
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 wouldn't come until the latter 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. 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 that were caused by stimulation of the perforant pathway. As expected, a single pulse of electrical stimulation to a fiber of the perforant pathway, the presynaptic fiber, caused an excitatory postsynaptic potential (EPSP) in a cell of the dentate gyrus, the postsynaptic cell. What Lømo didn't expect was that the postsynaptic cell's 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 fiber. When such a train of stimuli was applied, subsequent single-pulse stimuli elicited stronger, prolonged EPSPs in the postsynaptic cell. 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".
Timothy Bliss, who joined the Andersen laboratory in 1968, Andersen has suggested that the authors proposed "long-term potentiation" for its easily pronounced acronym, "LTP".

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.
   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. 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.
   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, 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. 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. Glutamate binding to the AMPA receptor triggers the influx of positively charged 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 doesn't 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're 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). 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 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

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 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 couldn't 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. 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. 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 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 couldn't 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."

Further Information

Get more info on 'Long-term Potentiation'.

External Link Exchanges

Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:

<a href="http://long-term_potentiation.totallyexplained.com">Long-term potentiation Totally Explained</a>

Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned.