Long term Potentiation (LTP)
(last updated May 1998)
A page from: Eric Hargreaves'Page O'Neuroplasticity
"Long-term Potentiation" or "LTP" is an enduring increase
in the efficacy of specific brain pathways resulting from the application of brief high frequency electrical
bursts. Currently, LTP is the reigning electrophysiological neuroplasticity phenomenon with which to model memory processes.
As such, it has been subject to periodic reviews and extensive summaries over the years
(Bliss and Collingridge, 1993;
Gustafsson and Wigstrom, 1990;
Teyler and DiScenna, 1984; 1987).
Because of its potential relatedness to learning and memory, many of the reviews have specifically focussed on how LTP may relate to learning, with much of the earlier appraisals far more positive(Morris and Baker, 1984;
Racine and Kairiss, 1987)
than some of the recent reviews
(Vanderwolf and Cain, 1994;
Shors and Matzel, 1997).
Yet, the commentary in response to the Shors and Matzel (1997) review, by some 20 different authoring groups, is still largely hopeful that LTP will provide insight into learning and memory mechanisms.
The "Hebb" synapse, a theroretical basis for learning
For some time, changes in synaptic efficacy, or how well neurons communicate with each other,
has been suggested as the cellular basis for encoding and storing information.
In fact, the idea that neural tissue will increase as a consequence of learning
has been around since the 1700s, but it was Donald O. Hebb, who first
posed a specific theoretical process by which this might occur
(Hebb, 1949). Hebb hypothesized that permanent
memory traces could be laid down by the sustained activation of
reverberatory circuits, or neural networks that would echo
and in effect hold the information after the event itself had passed.
A permanent change in the reverberatory circuit would occur if activated to sufficient levels,
thereby allowing the information to be more easily retrieved or remembered.
The neuroplasticity phenomenon of LTP, discovered some 20 years later, functioned in exactly this manner, such that
a test pulse of a fixed intensity, activating a specific set of synapses, after LTP, activated a far larger set of synapses.
Conversely, a test pulse set at an intensity much lower than the original fixed intensity could now activate the original specific set of synapses.
History of LTP
In examining the functional circuitry of the hippocampus, during which specific
synapses were activated by brief afferent volleys or test pulses,
a group in Oslo Norway discovered that when applied in succession,
test pulses could subsequently activate either fewer or greater synapses,
dependent upon the interval between test pulses
(Andersen et al., 1966;
Lomo, 1966; 1971).
The latter of these phenomena in which "potentiation" occurred was then
studied more extensively, and what was initially called "frequency potentiation"
became "long lasting potentiation", and eventually Long term potentiation
(Bliss and Lomo, 1973;
Bliss and Gardner-Medwin, 1973).
At left is Dr. Tim Bliss one of the first scientists to formally report LTP in the early 70s.
The picture was taken in 1998 at the University of Otago, New Zealand.
The original reports were soon replicated by others who were already interested in the neuroplasticity phenomenon of
Douglas and Goddard, 1975;
Not too surprsingly, there was little distinction between the different phenomena at first,
and in fact the original LTP studies may have induced seizure activity.
One of the important developments in the early LTP research was the use of the tissue slice, an in vitro preparation
(Schwartzkroin and Wester, 1975;
Alger and Teyler, 1976).
In the slice preparation thinly cut sections of the brain are kept alive in a bath of artificial cerebral spinal fluid.
The development of a viable slice preparation was attempted by a number of groups throughout the fifties and early sixties without too much success.
Success was acheived in the mid-sixties by moving to a more simply structured part of the cortex (
Yamamoto and McIlwain, 1966).
The hippocampus, as part of "allocortex", a much older
and similarly simpler part of cortex,
made an ideal candidate for the slice preparation,
which Andersen and colleagues took advantage of in their functional analysis of hippocampus circuitry
(Skrede and Westgaard, 1971).
The slice preparation, once co-opted for LTP research, allowed the rapid advance in understanding the
underlying mechanisms of LTP,
since the in vitro composition of the perfusing bath
could easily, quickly, and reversibly be altered, and thus, the effects readily studied.
The Basics of LTP
(Hippocampus, Trisynaptic Circuit)
Although LTP was first studied in the hippocampus, and the majority of LTP research continues to be performed in this structure, LTP has been found throughout the limbic forebrain
(Racine and Milgram and Hafner, 1983)
and in locations as diverse as the deep cerebellar nuclei (Racine, Wilson, Gingell, and Sunderland, 1986) and the superior cervical ganglion of the spinal cord (
Brown and McAfee, 1982). A large body of research has also been accomplished using invertebrates, most notable of which is the aplysia or sea slug.
As indicated however, most of the LTP research has been within the
hippocampus, in one of several main afferent flow synaptic pathways known as the
The figure at left depicts a rat brain with the cerebral cortex above the hippocampus extirpated (removed), such that the hippocampal formation of the left hemisphere is exposed (in purple).
Additionally, a transverse section has been cut and expanded to reveal the main afferent monosynaptic pathways, of which two are highlighted and identified (Perforant path to dentate gyrus and CA3 Schaffer collaterals to CA1 stratum radiatum).
Evoked Potentials (EPs)
Stimulating and recording electrodes placed on any of these main pathways can evoke and record a clear physiological response known as an "evoked potential" (EP), which is also displayed in the figure.
Thus, applying a brief afferent volley to the perforant path fibres will depolarize, and if strong enough synchonously discharge, the granule cells in the dentate gyrus.
Typically, two measures are taken from the EP, which function as indices of synaptic transmission between the entorhinal cortex and dentate gyrus.
First, the Excitatory Post-synaptic Potential or "EPSP", which represents the number of granule cells synchronously depolarizing.
The EPSP is measured as rise/run or slope, such that the steeper the slope, the greater the number of granule cells depolarizing.
If the afferent volley or test pulse is strong enough to fire the granule cells then a sharp deflection or "spike" opposite in direction to the EPSP
appears. This is the second indice, known as the extracellular Population Spike or "Pop-spike"
and is measured as either an amplitude or an area. As with the EPSP... greater pop-spike amplitudes reflect greater number of granule
Additionally, the negative peak of the pop-spike represents the modal number of granule cells firing, and the width of the pop-spike
represents the degree of synchrony among the granule cells firing (how much the cells all fire at once or are slightly spread out over time).
As indicated at the beginning, LTP results from the application of brief high frequency electrical bursts.
Before going over some of the specific induction parameters, it is worth mentioning that it can be induced chemically as well.
This is done by a very focal administration of drugs that either inhibit the inhibitory cells (disinhibiting the cells to be potentiated), or by directly exciting the cell population to be potentiated.
However, attempts to chemically induce LTP often result in afterdischarge or epileptiform activity, and therefore are more akin to
Kindling or Kindling induced Potentiation (KIP: Racine and Cain, 1992).
Below is an example of an LTP session that I recorded at McGill (July '96).
Baseline measures are taken prior to LTP induction, to ensure stability of the recording and to provide a starting point from which potentiation occurs.
The EP displayed at the left of the figure was one of the last sweeps recorded prior to LTP induction.
In this example the test pulse intensity used to evoke the baseline measures was approximately 25-35% of the maximum response.
LTP was induced at time zero.
The EP displayed in the middle was recorded within the first few minutes following LTP induction.
Note that there is at least a five-fold difference between the baseline pop-spike and the potentiated pop-spike.
The stability and decay of the potentiation was followed for two and half hours, at which time the session was terminated.
The EP displayed at the far right of the figure was recorded as one of the final sweeps of the session.
LTP induction parameters vary quite a bit in the literature, but the individual pulses that make up the pattern are fairly consistent,
ranging from 150 - 250 microseconds in duration (per phase). Often biphasic pulses are used instead of monophasic pulses in order to balance the overall current being delivered to the tissue.
However, short term studies still often utilize monophasic stimulation, since researchers are not concerned about hyperpolarizing or depolarizing the tissue surrounding the stimulating electrode, due to the works' brevity.
Whether or not the stimulation is monopolar or bipolar, that is, delivered against a single pole and a ground, or oscillated between two poles of the same bipolar stimulating electrode is also variable,
and no clear distinction between the effects of the two methods has been made. The intensity or amplitude of the pulses making up the LTP bursts is typically high, often
twice that of the individual test pulses used in assaying the synaptic efficacy of the pathway.
Increasing the stimulation intensity is either done by increasing the amplitude of the pulses within a tetanizing burst,
which is by far the most common method, or alternately by increasing the individual pulse duration of those pulses in the tetanizing burst, as is done in few labs
(Abraham et al., 1995;Jeffery, 1995).
However, series of ascending current intensities have been used in attempts to ascertain
changes in LTP induction threshold
(Robinson and Reed, 1992).
Individual pulses are sequenced together and delivered as repetitive brief bursts, or singular trains of up to several seconds in duration.
The singular pulse trains are more often used in anaesthetized preparations, with frequencies around 100 to 200 Hz.
However, even in anesthetized preparations these parameters have caused afterdischarge
(Warren, Humphreys, Juraska, and Greenough, 1995;
Racine and Cain, 1992).
As such, most researchers use higher frequencies, and briefer bursts in chronic behaving preparations.
That brief bursts (20msec) of higher frequencies (400Hz) did not provoke seizure activity
was the main finding of one the early LTP papers providing the basis for the divergence between LTP and Kindling phenomena
Both the number of high frequency burts, and intervals between them vary greatly.
However, the patterning of LTP induction is becoming of interest since greater potentiation has been found when modelled after EEG patterns intrinsic to the structure being potentiated, than
when the pattern intentionally mismatches the EEG pattern
(Larson, Wong and Lynch, 1986;
Larson and Lynch, 1986;
Staubli and Lynch, 1987).
The actual duration of LTP also varies greatly with its induction parameters, and the earliest claims suggesting
that LTP lasted for several months were probably confounded with seizure activity
(Bliss and Gardner-Medwin, 1973;
Staubli and Lynch, 1987;
Racine and Cain, 1992).
However, LTP can last at least several weeks
Racine and Milgram and Hafner, 1983),
although studies rarely record LTP's full decay.
Staubli and Lynch (1987) using a theta burst pattern of tetanizing stimuli in CA1 of the hippocampus have argued that the resultant LTP did not decay,
and that whenever drop off in the recordings was observed it could be attributed to shifts in the electrode positions.
Below is one of the "big LTP" protocols I'm currently using at the University of Otago (Aug '97).
Note that the EPSP decays back to baseline within days, whereas the pop-spike decays within weeks.
If one also does a quick calculation of percentage change over baseline, it should be quickly realized
that the EPSP also exhibits less potentiation then the pop-spike, which in itself has been a phenomenon of study known as "E-S" potentiation, standing for EPSP-Spike
(Collingridge and Singer, 1991).
Of course, LTP experiments done with the in vitro slice preparations are by necessity brief,
being only hours in duration. This is simply due to the fact that the slices cannot be healthily sustained much over 10 hours.
Mechanisms of LTP
Since the original reports of LTP in 1973, much has been done to elucidate the underlying mechanisms by which LTP is induced and maintained. As such, the rapidly accumulating results have been the subject of periodic reviews over the last decade
(Bliss and Collingridge, 1993;
Gustafsson and Wigstrom, 1990;
Teyler and DiScenna, 1984; 1987). Much of the understanding of what mechanisms underlie hippocampal LTP has come from the in vitro slice preparation and the examination of the CA3 pyramidal cell Schaffer collateral to CA1 pyramidal cell monosynaptic pathway
(Collingridge and Singer, 1991).
The transmitter system in the CA3 Schaffer collateral to CA1 pyramidal cell pathway depends on the excitatory amino acid glutamate
(Collingridge, Kehl, and McLennan, 1983b;
Olverman, Jones, and Watkins, 1984;
Storm-Mathisen, 1978). In keeping with Watkins and Evans
(1981) classification scheme there are n-methyl-d-aspartate (NMDA), kainate, and quisqualate excitatory amino acid receptor subtypes. Functionally however, this classification scheme appears to cluster into NMDA and non-NMDA excitatory amino acid subreceptor types, based on the specificity of available antagonists
(Lester Herron, Coan, and Collingridge, 1988;
McLennan, 1989). As such, non-NMDA receptors appear to be activated during normal synaptic transmission, while NMDA receptors appear to be activated under special circumstances, in particular those that occur during the induction of LTP
(Bliss and Collingridge, 1993;
Collingridge Kehl, and McLennan, 1983b; 1983c; 1984;
Harris, Ganong, and Cotman, 1984). However, it has been shown that a small NMDA mediated component of low frequency synaptic transmission does occur
(Davies and Collingridge, 1989;
Lambert and Jones, 1989; 1990;
Andreasen, Lambert and Jensen, 1988).
Thus, in those hippocampal pathways that utilize the excitatory amino acids, LTP induction can be blocked by competetive NMDA antagonists, most notably APV
(Bliss and Collingridge, 1993;
Collingridge et al., 1983c;
Errington, Lynch and Bliss, 1987;
Harris, Ganong, and Cotman, 1984;
Morris, Andersen, Lynch, and Baudry, 1986), but not by blockade of non-NMDA receptors antagonists such as 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX)
(Davies and Collingridge, 1989).
The special circumstances that occur during the tetanic stimulation that activate the NMDA subreceptor are the sufficient depolarization of the membrane, which may in part occur due to the depression of inhibitory responses
(Davies, Davies, and Collingridge, 1990;
Collingridge, 1989). As a result, LTP can be affected by the intracellular injection of depolarizing or hyperpolarizing current
(Collingridge, Herron, and Lester, 1988a;
Malinow and Miller, 1986;
Wigstrom, Gustafsson, Huang, and Abraham, 1986), or by reductions in inhibition through the application of GABA antagonists
(Davies and Collingridge, 1989;
Dingledine, Hynes, and King, 1986;
Herron, Williamson, and Collingridge, 1985).
Occupation of the NMDA receptor complex by glutamate following afferent fibre stimulation results in expulsion of Mg2+ from the NMDA ion channel making it permeable to Ca2+
(Herron, Lester, Coan and Collingridge, 1985b;
MacDermott, Mayer, Westbrook, Smith and Barker, 1986;
Mayer, et al., 1984;
Nowak, Bregestovski, Ascher, Herbet, and Prochiantz, 1984). Therefore, alterations in Mg2+ concentration also affect LTP-induction/NMDA-activation
(Coan and Collingridge, 1985;
Herron et al., 1985;
Huang, Wigstrom, and Gustafsson, 1987), as do alterations in Ca2+ concentration, either extracellular or intracellular
(Dunwiddie and Lynch, 1979;
Harvey and Collingridge, 1992;
Lynch, Larson, Kelso, Barrionuevo, and Schottler, 1983;
Obenaus, Mody, and Baimbridge, 1989;
Turner, Baimbridge, and Miller, 1982).
The intracellular influx and release of Ca2+ signals an enzymatic cascade, in which calpain, protein kinase C, type II calmodulin-dependent protein kinase ( -CaMKII), and tyrosine kinase have all been implicated
(Bliss and Collingridge, 1993).
Electron microscopy had revealed structural changes after LTP, in the number of synaptic-spine contacts, and in the shape of the spine heads
(Greenough, and Chang, 1985;
Lee, Schottler, Oliver and Lynch, 1980). These structural changes after LTP were found to be accompanied by protein synthesis
(Duffy, Teyler, and Shashoua, 1981). Thus, incubation of hippocampal slices with protein synthesis inhibitors prevented LTP (
Stanton and Sarvey, 1984) and in vivo administration of anisomycin prevented a late phase of LTP
(Krug, Lossner, and Ott, 1984). Recently it has been shown that the late phase of LTP requires newly synthesized proteins (
Frey, Krug, Brodemann, Reymann, and Matthies, 1989;
Otani, Marshall, Tate, Goddard, and Abraham, 1989).
LTP and Learning
Is LTP related to learning? This of course is the big question, and was recognized, albeit very cautiously, in the first LTP papers
(Bliss and Lomo, 1973;
Bliss and Gardner-Medwin, 1973).
Today, the answer still remains unknown, but is becoming more hotly debated.
Previously, the answer was simply unknown, and there was no debate since everyone hoped that there would be a great deal of overlap between LTP and learning.
This is largely because the idea of increased communication between cells as the physiological basis of learning, intuitively makes a great deal of sense.
In fact, it was such a commonly accepted idea that there was no mention of Hebb's
(1949) specific postulation in the LTP literature for over 5 years.
Future sections will discuss...
- LTP-NMDA-Learning Hypothesis
Meanwhile, you can always peruse the less detailed section concerning
my role in determining whether LTP and learning have anything to do with each other...
Links to Canadian Scientists, who do LTP Research
(last updated July 2007)
Not too surprisingly, there is a lot of overlap between scientists
who study Kindling and scientists who study LTP.
Note that this is not necessarily a list of all LTP researchers, just my list.
The list of all LTP researchers would be several hundred people.
Coming from Canada, my list tends to focus on Canadian researchers, with a few deviations to New Zealand, where I also worked.
If you wish to be added, just e-mail me at:
Cliff Abraham, University of Otago, New Zealand.
Gyorgy Buzsaki, Rutgers University, Newark, New Jersey, USA.
Peter Cain, Full Professor, University of Western Ontario, London Ontario.
Brian Christie, University of British Columbia Medical School @ Victoria, Victoria, Canada.
Mike Corcoran, University of Saskatchewan, Saskatchewan, Canada.
Stan Leung, University of Western Ontario, London Ontario.
Gary Lynch, University of California Irvine, Irvine California.
Ron Racine, McMaster University, Hamilton Ontario.
Matthew L. Shapiro, Mt. Sinai School of Medicine, New York, USA.
Patrick Stanton, New York Medical College, Valhalla New York.
Cam Teskey, University of Calgary, Alberta
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