Talk:Long-term potentiation

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Contents 1 Drug usage to stimulate and increase learning 2 Tetanic stimulation 3 Rewrite 4 Question 5 Question II 6 Three more questions 7 One question 8 Greetings 9 LTP Worldview 9.1 reply 10 Wikipedia???? 11 Early and Late Phase LTP 12 coincidence detector? 13 Quick question 14 Cooperativity vs. associativity 15 Thanks 16 The role of CREB 1 17 merge tag removed 18 Definition of Associative LTP 19 Don't Like First Sentence 20 Am I right to include Timothy Bliss as a co-discoverer? 21 Behavioral memory

[edit] Drug usage to stimulate and increase learning

I was reading some information on drugs used to increase the learning inside of animals that has to do with LTP. I don't exactly know too much about this subject since it seems somewhat brand new to me on a biochemical level.

Does anyone have information relating to the withdrawal effects on subjects that had taken in the drug? Did they show a lack of an ability to learn afterwards? What side effects did such a drug have? --Cyberman 17:56, 10 October 2005 (UTC)

[edit] Tetanic stimulation

What is "tetanic stimulation"? Is it just a high-frequency sequence of stimulations? AxelBoldt 21:41, 9 Sep 2004 (UTC)

Yes. --Diberri | Talk 22:05, Sep 9, 2004 (UTC)

Ok, what kind of frequencies are we talking about here? AxelBoldt 04:52, 11 Sep 2004 (UTC)

IIRC it's often a 5 x 100 Hz protocol (five 100-or-so-millisecond pulses at 100 Hz). I'll try to find a reference and post it here. --Diberri | Talk 23:41, Sep 11, 2004 (UTC)

[edit] Rewrite

I've just done a massive rewrite of the page in an effort to bring everything up-to-date with current studies of NMDA-dependent hippocampal LTP. In doing so, I've referred to journal articles using the syntax (PubMed ID), but haven't had time to apply the suggestions of Wikipedia:Footnotes. (If one checks the page history, they'll find that I did try to add footnote links, but I used the wrong CSS ID in the <sup> tags, so I got frustrated and gave up, at least temporarily :-) Incidentally, if anyone wants to tackle the task of adding ap

propriate footnotes (and citations under the "References" section), by all means feel free -- I'd very much appreciate it! For now I hope that readers find the rewrite more useful than the previous version. Best, David Iberri | Talk 00:26, Nov 16, 2004 (UTC)

Hi David, thanks for letting me know about the rewrite. I read it and learned a lot, again. Here are a couple notes that came to mind. I don't really know enought to fix these myself.

• In the earliest experiment showing LTP, was it done in vivo or in vitro? Generally, a section about how one conducts LTP experiments today in vivo and in vitro would be nice.
• Like I mentioned above, it might be good to give the frequencies typically used in experiments.
• In the section about non-associative LTP, it is mentioned in passing that associative LTP requires two stimuli, but the section about associative LTP does not make that clear.
• In the section about properties, are we really only talking about NMDAR-dependent LTP? If not, it would be good to give the section with the high level properties first, before going into biochemical details.
• I assume CREB only acts postsynaptically? This should be made clear. NO acts on both cells?
• The pictures of the synapses would be clearer if presynaptic and postsynaptic cells were labeled.
• The picture of the brain is a bit unclear: where's front and back?

Cheers, AxelBoldt 01:30, 29 Nov 2004 (UTC)

If I may be of help with your some of your questions (Synaptidude).

1. Bliss and Lomo did their original experiments in vivo in the dentate gyrus. I can't remember if if was rat, guinea pig or rabbit. (I checked, it was rabbit)
2. Typically 100 Hz tetanus for 1 second is the "standard" LTP inducting stimulus (often applied multiple times). Theta burst where a series of short tetani spaced to take advantage of inhibitory refractoriness is another way. I'd be willing to bet that today the most common method of inducding LTP is the so-called "pairing" protocol, where the postsynaptic cell is artificially depolarized while low frequency presynaptic stimuli are applied (pairing postsynaptic depolarization with presynaptic stimuli).
3. I've not yet read the section on non-associative LTP, but I'm assuming this means the LTP that has been seen by ultra-high frequency tetanus. This is believed to be mediated by postsynaptic voltage-dependent calcium channels, and thus requires only postsynaptic depolarization.
4. NMDA-dependent LTP is the "primary" form of LTP. Almost all the known LTP in the brain is NMDA-dependent. Non-associative LTP is not NMDA dependent (although there is some controversy here) and makes only a tiny contribution to changes in synaptic strength. Mossy fiber LTP is entirely presynaptic (again, some controversy, but I'd bet heavily on this) and not NMDAR dependent, but it occurs only in anatomically restricted (and synapse type restricted) areas.
5. I'm going to leave CREB alone. I'm not a big supporter of the CREB hypothesis. I believe the conclusions on this have outrun the actual supporting data.

[edit] Question

Hi, i am layman and i am not sure whether i understand this sentence right:

Though a single presentation of the stimulus is USUALLY not sufficient to induce LTP, repeated presentations cause the postsynaptic cell to be progressively depolarized.

Does it mean that that some things are written to our memory completely by chance? that some quick glance can be stored in our memory just because of rigtht polarization of the postsynaptic cell? and on the other hand something we want to remember may not be joined by right polarization and therefore we just forget it?

thank you for a respond tomas

Whether or not chance has any effect on LTP induction is largely a philosophical question. In science, when the parameters aren't sufficiently understood, variations are often attributed to chance for convenience. I suspect this is because scientists are wary of violating Occam's Razor. Anyway, by usually I was trying to account for some experiments that have elicited LTP with a single stimulus, while the vast majority of trials require multiple high frequency stimuli; I didn't intend to imply that chance alone can induce LTP. At most, chance plays a part in LTP induction, but again that's largely because many (if not most) of the details of LTP are as yet unknown.

As for a quick glance coupled with the right postsynaptic polarization leading to learning, remember that LTP and learning are not equivalent. Learning is behavioral (and thus deals with the whole organism) while LTP is cellular (and thus deals only with cells). A glance is the result of millions upon millions of cells in the visual cortex and elsewhere processing visual stimuli. The brain's got ways to reduce the contribution of single cells to memory formation. (Some of these ways prevent us from storing things like frame-by-frame memories. Just imaging how devastating things would be if the whole of your memory was consumed by the individual visual frames you perceive throughout your day -- you'd never be able to commit any useful information to memory. Hardly an adaptive strategy!) So a single postsynaptic cell being polarized just right wouldn't have a significant impact on whether a particular split-second of our vision gets stored away. (At least in humans. In other animals with simpler nervous systems, LTP in a single cell can have remarkably significant effects; cf Aplysia.)

Now if we talk about single cells rather than organisms, and LTP (cellular) rather than learning (behavioral), then things are a bit different. Single synapses, and thus single cells are very important and the polarization of an individual cell is a big contributor to LTP. But even then, you'd be hard-pressed to find a reputable source that would attribute LTP in single synapses to chance alone. Best wishes, David Iberri | Talk 18:21, Dec 27, 2004 (UTC)

[edit] Question II

thanks for a quick respond- i am writing some school work about memory and i have got a few questions about LTP( maybe answers are written in your article but i am not from english speaking country and therfore i do not understand everything:-(

1. does LTP have proven and clear connection with learning and information storing process? am i right if i say that increased calcium level in dendrite results (after many chemical reactions, and if everything goes right) into creation of neuron network responsible for remembering of some piece of information ???

2. this neuron network can be located anywhere in the brain according to character of stored information-but if i understood it right not all parts of brain have LTP ability

3. how are those neurons in this network connected? and how are new neurons representing new information related to original added to this network? does LTP still plays role here?

thanks for your understanding. i know that my questions may look simple but i am only high school student and so i am doing as much as i can, to get into this problem...

so if you have some time please answer my questions it will help me a lot:-) THANK YOU VERY MUCH --R0SI 21:51, 27 Dec 2004 (UTC)

You're very welcome for the responses. I'm just one of many Wikipedians who is more than happy to help. As for not understanding everything in the article, I'm partially to blame; it's written from too technical a perspective, and that should be cleaned up when possible. When I get some more time I'll be sure to clarify things as best I can. (Thankfully, this being a wiki, the onus isn't completely on me to make sure the article is in tip-top shape, though :-) For now, I'll do my best to answer your questions:

1. I tried to address this a bit in the article under the section LTP and behavioral memory. As far as I know, no one has yet demonstrated a causal role between LTP and behavioral learning. I'm making a point to say behavioral learning here, not just any type of learning, because in the laboratory, scientists can induce LTP to cause some types of learning. But nobody's shown that LTP is the way organisms learn on their own.
   
   There have been plenty of correlational studies looking at LTP's causal role in behavioral learning, though. In these experiments, scientists often give animals drugs that alter LTP before teaching them a task. Then they compare the changes in LTP to the changes in learning. For example, blocking the NMDA receptor (which in turn blocks LTP) impairs spatial learning in rats. So when LTP is impaired, spatial learning is impaired too. It's tempting to say that LTP therefore causes memory formation, but that would be incorrect. A common saying is that "correlation does not imply causation," meaning that just because two things happen together doesn't mean that one causes the other (see spurious relationship for more on that). So no, there hasn't yet been any "proven and clear connection with learning" unfortunately.
   
   As for the question about calcium, are you asking if calcium results in the formation of new neurons in a network capable of storing memories? If so, there's very little new neuron growth in humans after about 8 years old, so you can see that new cell growth couldn't be the way memories are stored. Current thinking is (roughly) that memories are stored in synapses, which are dynamic (i.e. they be created/destroyed/modified relatively quickly), not neurons themselves. So you might say that calcium induces LTP and (presumably) ultimately alters synapses in existing networks for memory storage.
    
2. You're right, not all areas of the brain are capable of LTP. But LTP has been demonstrated in many areas of the brain implicated in learning (e.g. amygdala, hippocampus, cortex). One popular working model of learning says that the hippocampus is the gateway to long-term memory; once the hippocampus has registered a memory destined for LTM, it propagates that memory to relevant portions of the cortex. So for example, when a rat learns how to navigate a maze, it might keep a visual representation of the maze in the visual cortex, a memory of what sounds it encountered when navigating the maze in its auditory cortex, etc. (I presume that's what you mean by the brain storing memories in regions "according to character of stored information"). When the memory is recalled, all of these various cortical areas are activated to reconstruct the rat's memory of the maze.
    
3. I'm not sure I understand your question about how neurons are connected. Are you talking about neurons in the cortex where these long-term memories are stored? If so, nothing's changed here; the connection is still made through chemical synapses. The changes that have occurred in these neurons is attributed to LTP, so you'd expect to find enhanced activity at existing synapses, growth of new synapses between existing cells, etc.

Ideally most of this would be covered at Memory#The physiology of memory or even branched off into its own article, but no one has got around to it yet. Until that day (and even after!) feel free to keep the questions coming, and please don't think you're asking anything invalid or too simple. Your questions are absolutely always welcome. Best wishes, David Iberri | Talk 22:59, Dec 27, 2004 (UTC)

[edit] Three more questions

thank you for your answers for my question- they really helped ma a lot. but i have got three more

1. is it correct if i say that one HYPOTHESIS, explaining process of learning is LTP...etc. hypothesis is right word even if you said that connection between LTP and memory formation was not proven and it is probable that those two things have nothing in common?

2. that tetanic stimuli is in fact visual/audio stimuli (something we saw/hear) but encoded into sets of signals with frequency about 100Hz? this happens as information pass through eye or ear?

3. you write that hippocampus propagates memory to relevant portions of the cortex-it is responsible for connecting memories of various characters(audio/visual). what is the mechanism of this. i mean if those informations are stored- one in visual and one in auditory cortex the neurons or esp. dendrites and axons have to be few centimeters long. am i right?

nice day and thak you for all--R0SI 18:52, 28 Dec 2004 (UTC)

1. Yes, one hypothesis is that LTP is the underlying physiological mechanism of behavioral learning in animals. In my opinion, it's highly unlikely that LTP and learning are unrelated.
2. That's a good question. LTP experiments in the laboratory typically use tetanic stimulation in the range of 100Hz to induce LTP, but there are few ares of the brain capable of reaching those levels of stimulation in vivo. Recently the hippocampus, if I'm not mistaken, has been observed using these same frequencies, but whether it's for the purpose of LTP is still uknown.
3. Very little work has been done in the area of memory recall (compared to the amount of work done on memory formation), so it's difficult to point to a precise mechanism. What I can tell you is that the hippocampus' main output is the subiculum and entorhinal cortex, which communicate messages from the hippocampus to the rest of the cortex. The length of these axons would be on the order of several centimeters. Dendrites, on the other hand, would tend to be a bit shorter. --David Iberri | Talk 21:00, Dec 28, 2004 (UTC)

[edit] One question

What is plasticity-related proteins? --Daxue | Talk 04:20, 8 Jan 2005 (UTC)

A: This link is useful for understanding plasticity or Synaptic plasticity. --Daxue | Talk 09:33, 8 Jan 2005 (UTC)

[edit] Greetings

Hi Big Dave. I'm new to WP, but I naturally zeroed in pretty quickly on your LTP article (being a scientist who works in this area). You've done a really nice job with it. I hope you don't mind if I pop in now and again to edit. I've done some already. This is what WP is all about, right? Anyway, just wanted to say "I come in peace ;-)"

Hey there and welcome to Wikipedia! Thanks for the compliments. I'm really looking forward to your edits. It'll be great to have an expert at the helm ;-) --David Iberri | Talk 00:13, Jun 23, 2005 (UTC)

[edit] LTP Worldview

Hey Big Dave. Thanks for the help with the wiki defs.

As I said before, I think you've done a really nice job on the LTP article. It is well-written, well-documented, well-organized etc. Yet, as I read it, I find myself frustrated by something I couldn't quite put my finger on. As I corrected a few of what I considered "factual errors" in the piece, I realized that the reason I find myself disagreeing with many of the "facts" is that you've written the piece mostly from a Kandelian point of view. I notice that 10 out of 31 of your notes are to Kandel references. As a researcher in this field, and someone who has a pretty good feeling for its pulse, I can tell you that most of the really reputable labs working on LTP think that when it comes to LTP, that Kandel is........what's the scientific term for this?.........oh yeah!........Full of Crap. Many if not most of his LTP findings are believed by no one but himself and his own people. His papers are rife with fundamental experimental errors, overreaching interpretations, data bent to fit the hypothesis, etc. IMHO, in writing a review of the LTP literature, you could throw out everything produced by Kandel's lab and your review would be better for it. I find myself extremely tempted to rewrite large tracts of your article from a Nicollian, Malenkaian, Malinowian, Collingridgian, Madisonian, Huganirian, Kauerian, Issacian, etc-ian.....ok from a more mainstream and broader point of view. Part of the trouble is that you are writing about things that still have ragged edges. That scientists are still unsure about or are still arguing about. But on the other hand, I find myself reluctant to tear apart what is really a beautiful article (with above noted exception). You obviously put a lot of effort into it. So what I'm going to do instead is this: when I find something I don't like, I'm going to put a link in your article called "point of controversy" that will refer to a separate article where the pro's and con's of a particular issue are disussed.

If you'd enjoy taking a stab at this yourself, I'd suggest that a good goal to shoot for is too achieve a two to one ratio in references by Nicoll vs references by Kandel. Nicoll and his scientific offspring have done more to nail down the mechanisms of LTP with quality reproducible experiments than just about anyone.

I'll just leave you with this thought. Just because it's in the literature doesn't mean it's true. This may particularly be the case for the LTP literature where it sometimes seems that pretty much everything has been shown to be both true and untrue at least once. This may more often be the case when the senior author is an influential and powerful scientist (maybe even a Nobel Prize winner!) who can pretty much bully any paper he wants into a good journal over the objections of his peer reviewers.

Synaptidude

Thanks for your comments. This article will benefit greatly from the experience of an active LTP investigator like yourself -- one who not only has a better understanding of the processes of LTP, but also its culture and controversy. As my only exposure to LTP was in the classroom, I have very little experience with the latter two -- which is no doubt evident from my contributions to the article.

I am aware, however, of some of the strong disagreements between several LTP camps. Interestingly (or not), I studied under one of Kandel's former postdocs, David Glanzman, who (as he tells it) fiercely disagreed with Kandel's idea of exclusively presynaptic mechanisms of LTP induction and expression. So from the get-go I was skeptical of Kandel and his group, becoming more so after reading Hawkins' dismissive reply to Lin and Glanzman's work that suggested a Hebbian contribution to LTP in Aplysia. All that's to say I had a pretty strong bias against Kandel as I began writing this article. My bias wasn't to the point that I'd believe that "no one but himself" agrees with Kandel's research (that's a bit of an overstatement), but I was and am doubtful of some of his work nonetheless.

Yet as you note, Kandel's work is ubiquitous and Kandel is considered an authority on LTP research (you're right -- the Nobel Prize doesn't hurt). That his research winds up in nearly every peer-reviewed journal, textbook, and mainstream publication is a testament to Kandel's pervasiveness. And it's these facts that led me to doubt my own anti-Kandelian tendencies such that I felt a need to pull back on the reigns in an effort to maintain NPOV. Maybe I pulled too far? ;-)

Certainly publication does not imply truthfulness. I think this is merely a cultural misunderstanding coupled with the difficulty in writing an encyclopedia article about a debated topic like LTP. I understand your reluctance to tear apart this article, but that's the spirit of Wikipedia! :-) So rather than branch out discussions of controversial points (e.g. LTP induction), please incorporate those into the article proper. Likewise, if you find a section is particularly riddled with inaccuracies, move it to the talk page (possibly replacing it) for discussion. Also, I agree that we should try to incorporate more work from Nicoll (et al, particularly Malenka and Malinow -- their reviews are especially good).

Incidentally, I wasn't aware that so many of Kandel's experiments aren't reproducible. How (references) have you determined this? This, along with many of the other points you mentioned, is making me think a "Controversies in LTP research" section would be quite appropriate.

Cheers, David Iberri | Talk June 28, 2005 20:47 (UTC)

[edit] reply

Hey Big Dave,

You are right about one thing (well more than one thing ;-). My "no one but him" statement was an overstatement. I was thinking about this before I read your reply. I'm trying to think of a way of putting this that would be more accurate, and I suppose it would be: Many if not all of the reputable labs working at the center of the mechanism of NMDA-dependent LTP, believe that Kandel's group is wrong about most of what they've published on LTP.

Here's some backup.

1) On the question of the expression of LTP being pre- or postsynaptic: This debate raged for years without much in the way of conclusive evidence one way or the other. In the last five years, it's pretty much become everyone against Kandel and Stevens (and even Stevens seems to be backing off). I could go through and give you specific references, but there are many and that would be tedious.

But on another LTP related issue, here are some good examples of failure to replicate.

Example 1:

[1]

This is an extraordinary paper. Several years ago, Kandel was pushing the idea that Nitric Oxide mediated LTP through activation of a cGMP-dependent protein kinase (G-kinase). Nobody else who worked on this could reproduce his results. In an attempt to "stop the madness", four labs did something that is practically unheard of. The labs of Nicoll, Malenka, Malinow and Lisman agreed each to try to reproduce Kandel's experiments separately. They met ahead of time to make sure they all agreed on the details of Kandel's experimental protocol, and then they all went to their own labs and did the experiment without communicating with each other. After the experiments were completed, they got back together and compared results. They all four got the same thing. They could not reproduce the Kandel result. I know of this not just from reading the literature, but because they asked me to join in this effort as well. I declined only because I'd already published a failure to replicate this result.

Here is Kandel's original paper:

[2]

Example 2: ..An example not of failure to reproduce, but rather over-reaching interpretation on incomplete experiments.

This paper:

[3]

purports to show that Carbon Moxoxide is necessary for LTP (as a retrograde messenger). The problem is that they used only a single inhibitor of Heme Oxygenase (the enzyme that produced CO in the brain). This just does not conform to accepted practice. You need control experiments. We published a paper where we actually reproduced his finding, but the control experiments clearly indicated that Heme Oxygenase was not the relevant target of his inhibitor, rather those compounds that inhibited Nitric oxide synthase worked, while those that exclusively inhibited Heme oxygenase didn't. This wasn't the worst part. The worst part was that his lab then replicated my findings exactly, but (with a justification I to this day can't understand) interpreted it as supporting his previous conclusion rather than refuting it (as it does). Fortunately (I guess), he never published it. He just presented it at meetings.

Example 3: His lab has published numerous papers showing that cAMP analogues are sufficient to produce LTP. The usual suspects (see #1 above) have tried to reproduce this result and can't

Example 4: an example of failing to do the most basic control experiment. There is a lot of doubt in the LTP community about so-called "late-LTP". Not so much whether it exists or not (several labs have shown this), but rather whether it exists as a independently inducible entity, rather than just an natural follow-on to early LTP. He has based much of his work on his purported ability to induce the two phases separately (thus, being able to show the effects of experimental manipulation on one phase or the other). He induces E-LTP with a weak or brief tetanus, while E-LTP + L-LTP is induced by a strong or longer tetanus. The problem is that the ability to induce LTP has a failure rate. This failure rate goes down with stronger tetani. If you average the failures to get LTP in along with the successes (as he does), you will get what appears to longer-lasting LTP with the stronger tetanus. But what he is seeing is not LTP that lasts longer, but rather LTP that occurs more often. The test for this is simple. Simply average only the successes in inducing LTP. When you do that (as several labs have, you find that weak and strong tetani produce LTP of exactly the same duration (long). He is certainly aware of this critisism, but he can't do the proper analysis, because (IMHO) he's got too much invested in it.

Say Hi to David (I've met him).

Synaptidude 29 June 2005 00:30 (UTC)

[edit] Wikipedia????

Hi there, I'm new to Wikipedia and stumbled across this article just the other day. Are regular folks such as myself welcome to edit the main text of articles posted on the Wikipedia website? If that is the case, what is the safegaurd against fraudulent information being posted? As far as citing sources goes: How do we do it? Forgive me if these questions are answered somewhere else on the Wikipedia website, it's just that an open source encyclopedia database is such a revolutionary concept that I am a little taken aback.

Hey there! And welcome to Wikipedia. Yes yes yes!!!!! You are not only welcome, but encouraged to edit the text of articles. Go for it. Be bold The system is self-policing. If someone vandalizes, writes fraudulent stuff, nonesense, factually incorrect statements, bad grammar etc., someone else will edit it.

So have at it! Synaptidude 00:23, 15 July 2005 (UTC)

Oh yeah, if you want an example of this self-policing, go have a look at the talk page for creation science. We've been having a lot of fun over there basically arguing over the inclusion of a single word in the first paragraph ;-). Synaptidude 00:25, 15 July 2005 (UTC)

[edit] Early and Late Phase LTP

I have several questions regarding the deliniation of LTP into two distinct phases:

1) I understand that Early Phase LTP is the protein synthesis independent phase of LTP, meaning that the necessary components of synaptic plasticity are already present inside the cell. Are the various receptor subunits already assembled into functional receptors that are awaiting shipment to the dendritic branches, or do they have to undergo some level of processing before shipment?

LTP is expressed via the insertion of AMPA receptors into the extrasynaptic membrane and their subsequent diffusion into the postsynaptic membrane. This happens too fast for synthesis, assembly or transport to be involved. The receptors are preassembled in the ER, consitutively shipped to the dendritic spines where they are contained in recycling endosomes. Upon the induction of LTP, they are simply translocated into the membrane.

2) In reference to the aforementioned receptors/unassembled receptor subunits: Where are these units stored in the cell? What mechanism governs the release/transport of these units? I understand that CaMK II and PKA facilitate the insertion of these new receptors into the membrane. What I would like to know is how these receptors end up at the membrane in the first place?

This topic is still the subject of scientific investigation so the answers are not all known. But what appears to happen is that the receptors are moved from intracellular recycling endosomes into the plasma membrane via a vesicle-dependent exocytosis (kind of like transmitter release, but this time, the cargo is receptors, and they are in the membrane of the vesicle, rather than in the lumen.

3) Late Phase LTP is the protein synthesis dependent phase of LTP. After receiving the necessary signals, transcription occurs and is immeadiately followed by translation and thusly protein synthesis. Is it fair then to say that Late LTP serves mainly or perhaps solely to restock the neuron with the necessary components of plasticity? If so would it be fair to say that Late LTP is really just a homeostatic mechanism, keeping the cell stocked with the materials that it needs to performs it's duties? Do post synaptic changes occur as a direct result of L LTP or are the components of plasticity merely synthesized and left waiting for some later signal?

This is not really known, but it is believed that the protein synthesis is actually building new synaptic structure or new synapses. Some of us think that much of the work ::on L-LTP is BS.

4) How is it possible to activate E LTP but not L LTP? Doesn't the fact that L LTP cannot be induced without first inducing E LTP support the argument that L LTP is a rebuilding process and not a discrete type of LTP?

It is reported that E-LTP is induced by "weak" tetanus and L-LTP by strong. But IMHO it doesn't all add up. I personally believe that E and L are just different aspects of the same inseparable process. However, if you want the party line, read Kandel

Synaptidude 21:35, 18 July 2005 (UTC)

Thank you for your assistance with these questions

[edit] coincidence detector?

After further reading, I have some questions about the coincidence detector. How does the removal of the Mg++ ion from the NMDAR channel serve as a coincidence dector? If Ca++ is artificially inserted into the neuron will associative learning not take place unless the magnesium ion is also removed?

The more you can tell about this process the better.

Thank you for your assistance

coincidence detector

In terms of finding a neuronal substrate for learning, you need some sort of coincidence detector. Think Pavlov's dog. The dog learned that a bell meant food was going to be delivered because the bell was presented in coincidence with the food until the dog learned the association. So how could such coincidences be recognized by neural circuity?. One proposal is the the NMDA receptor serves as the coincidence detector. To understand this, you have to understand what TVP Bliss calls "The induction rule for LTP". The induction rule says that you need two things to happen simulataneously for LTP to be induced. Those two things are: 1) Binding of glutamate to the NMDA receptor, and 2) sufficient depolarization of the postsynaptic cell.

The reason that you need these two things to happen is because glutamate opens the gate on the NMDA receptor channel. But current can't flow through the channel because it is magnesium blocked. You also need sufficient depolarization to allow the magnesium to leave the channel. This allows other ions, in particular calcium, to flow through the NMDA channel. The reason that depolarization "works" is because the magnesium binding site inside the NMDAR channel is even with the plane of the plasma membrane and thus, is acted upon by the electric field of the membrane. When the membrane is depolarized, the electric field grows weaker and magnesium is not held as firmly in the channel, allowing it to escape.

The critical factor that induces LTP is the calcium that enters the cell through the NMDAR channel.

So the reason that this provides a coincidence detector is that it means that one synapse can help another synapse to potentiate. If you have a strong LTP inducing stimulus on one synaptic input, it not only meets the induction rule for that input, but it also depolarizes the whole postsynaptic cell. If a "weak" (i.e. not strong enough to induce LTP on it's own) input is activated at the same time, it releases glutamate onto it's own postsynaptic NMDARs. The channel opens, and IF BY COINCIDENCE THE CELL IS ALREADY DEPOLARIZED BY ANOTHER INPUT then the weak input will meet the induction rule, and hence will potentiate.

Back to Pavlov's dog. What if the infomation of "food" (known is classical pavlovian conditioning as the US (unconditioned stimulus)) is carried on the strong input, and the information on the bell (the CS or conditioned stimulus) is carried on the weak input. The bell means nothing to the dog, so the input remains weak. But if the food is consistantly paired with the bell, the strong and weak inputs get activated together, and the neural system is able to detect the coincidence between them because the stong input helps the weak input to potentiate.

See? Synaptidude 00:20, 21 July 2005 (UTC)

[edit] Quick question

Plasticity

I know that plasticity refers to the altering of connections between neurons, i just want to make sure that i understand all the different forms that plasticity can assume:

insertion of new receptors phosphorylation or movement of old receptors to increase efficacy increased dendritic spines and branching

did i miss anything??

Plasticity in the larger sense of biology means any change in a system that can be brought about by interaction of that system with it's environment. Synaptic plasticity refers specifically to changes that can occur at synapses in response to the environment, usually in response to synaptic electrical activity.

new receptors, old receptors, spine morphology etc, are aspects of plastic mechanism, but the term "forms" of plasticity, it is usually taken to mean a higher level. Forms of plasticity would be LTP, LTD, PPF, PTP, depotentiation, etc. The things you mention are mechanisms that might underly those forms of plastcity. For LTP, it is thought to be mainly movement of AMPARs into the membrane, while LTD is their removal. Phosphorylation it thought to be a trigger for the receptor trafficking. Spine and branching morphology changes are though perhaps to mediate longer slower forms of synaptic plasticity. Synaptidude 00:41, 15 August 2005 (UTC)

[edit] Cooperativity vs. associativity

Hi guys, great effort, great job! Just a remark I came across right now about the confusion of the terms cooperativity and associativity, both claimed to be different properties of LTP. Well, Bruce McNaughton, an electrophysiologist who contributed largely to the field and introduced the term "cooperativity" claims that to be the source of still ongoing confusion as for: there is no difference between cooperativity and associativity. The same occurs in your description of NMDA-receptor-dependent LTP and carries on with this. I think it's worth a fusion to stop muddling. Have a look at the references.

[4]

PMID 12740107

Bye, Tobi.

Associativity and cooperatively with regards to LTP are usually used to denote slightly different aspects of LTP, although both have the same underlying mechanism. Associativity is used to describe how one set of inputs can provide postsynaptic depolarization to another set of input to allow the induction of LTP in the second set. In other words, the association of a strong input and a weak one allows induction in the weak one. Cooperativity is usually taken to mean the number of axons within a given input that must be activated to get LTP at all. A few axons do not sufficiently depolarize the postsynaptic cell to induce LTP. It takes the simultanous activation (the coorperative activation) of many to get LTP.

In both cases, it is sufficient depolarization of the postsynaptic membrane potential to allow the unblocking of the NMDAR (by magnesium) that is the underlying mechanism.

So, they are the same thing, but usually taken to mean different aspects of the same thing. Synaptidude 00:36, 15 August 2005 (UTC)

[edit] Thanks

Just wanted synaptidude and all others who contribute to wikipedia for the awesome job you guys are doing explaining some fairly complex topics....thanks

ya'welcome! Synaptidude 18:35, 10 October 2005 (UTC)

More thanks! This article is incrediblely thorough + in-depth.

[edit] The role of CREB 1

I have read much of the role of CREB 1, that it is activated by the active subunits of PKA and that it goes on to regulate gene expression, my question is this: Have researchers pinpointed which genes are transcribed or what the end product proteins do inside the neuron? I understand that these genetic products relate to synaptic plasticity but exactly is produced?

The answer, for the most part, is 'no'. Experiments using gene arrays to capture and identify mRNAs produced, increased, or decreased after LTP have been failures. This is probably because brain tissue is so heterogeneous that the number of cells that have actually undergone LTP is very small compared to the number of cells in the tissue (e.g. Glia make mRNA, but are (probably) not involved in LTP.). There are lots of gene products that increase after strong activity (the early-immediate genes), but the role of these is unclear and they don't require LTP, only activity.Synaptidude 18:24, 10 October 2005 (UTC)

[edit] merge tag removed

I removed the merge tag (request to consider merging this article with LTP induction). I did this for the following reasons

• It has been there a long time, and there has been no discussion of the potential merge
• LTP induction is a stub that was written by me as a way of starting the process of moving some of the stuff in this article out to subordinate articles. This was done to try to get the main article under the 32K limit. I stoopped this process while waiting for discussion on the potential merging, but since there has been none, its, IMHO, time to think about getting the article under limit.

[edit] Definition of Associative LTP

The definition of associative LTP was dead wrong, so I corrected it. January 27, 2006.

[edit] Don't Like First Sentence

The first sentence sounds like LTP means something to do with physical strength. I think it should be changed but can't think of what to. --Username132 (talk) 19:50, 21 May 2006 (UTC)

I agree, and unfortunately I can't think of a great alternative either. For now, I've changed "long-lasting strengthening of the connection" to "long-lasting enhancement of the synapse". Though now that I think about it more, I don't like this either. You don't enhance a synapse, you enhance the strength of a synapse. Gah. Let's think about this some more... --David Iberri (talk) 14:08, 31 May 2006 (UTC)

How about:

LTP is the long-lasting enhancement in the activity efficacy of a synapse between two neurons.

? --David Iberri (talk) 16:56, 2 June 2006 (UTC)

[edit] Am I right to include Timothy Bliss as a co-discoverer?

I googled that Tim Bliss was a co-discoverer of LTP, and included him in the sentence about the discovery in 1966, but now I have doubts. If I was wrong, -revert my change. --CopperKettle 04:36, 12 August 2006 (UTC)

Most researchers I've spoken with (which admittedly isn't many) seem to regard Bliss as a co-discoverer, but they base that on the 1973 Bliss & Lomo paper that first characterized LTP. But based on Lomo's recent paper on the discovery of LTP, I'm fairly certain that Lomo made the initial discovery by himself in 1966, with Bliss joining the Andersen lab only in 1968. I'll revert your change for now, but feel free to continue the discussion here. --David Iberri (talk) 14:03, 12 August 2006 (UTC)

[edit] Behavioral memory

This one's just screaming to be added to the "relationship to behavioral memory" section: Whitlock J, Heynen A, Shuler M, Bear M (2006). "Learning induces long-term potentiation in the hippocampus". Science 313 (5790): 1093-7. PMID 16931756.  --David Iberri (talk) 04:28, 15 January 2007 (UTC)

Done, although it could use some refining. --David Iberri (talk) 19:26, 5 February 2007 (UTC)