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The Journal of Neuroscience, November 1, 2002, 22(21):9626-9634
Induction and Experience-Dependent Consolidation of Stable
Long-Term Potentiation Lasting Months in the Hippocampus
Wickliffe C.
Abraham1,
Barbara
Logan1,
Jeffrey M.
Greenwood2, and
Michael
Dragunow2
1 Department of Psychology, University of Otago,
Dunedin, New Zealand, and 2 Department of Pharmacology,
University of Auckland Medical School, Auckland, New Zealand
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ABSTRACT |
Long-term potentiation (LTP) is widely regarded as a memory
mechanism, but it is not known whether it can last long enough to
underlie very long-term memory. We report that high-frequency stimulation (HFS) paradigms applied to the rat dentate gyrus can elicit
stable LTP lasting months and up to at least 1 year. The induction of
stable LTP was sensitive to stimulation variables on the day of HFS and
was associated with phosphorylation of cAMP response element-binding
protein. The maintenance of stable LTP was also experience-dependent,
because it was reversed when animals were exposed repeatedly to an
enriched environment beginning 14 d post-HFS. However, stable LTP
eventually consolidated over time and became resistant to reversal,
because exposure to enriched environments 90 d post-HFS failed to
influence stable LTP maintenance. Thus, LTP can be shown to meet one of
the principal criteria for a very long-term memory storage mechanism.
However, under naturalistic environmental conditions, LTP may normally
be retained in the hippocampus for only short periods of time.
Key words:
long-term potentiation; memory; hippocampus; enriched
environment; CREB; depotentiation; NMDA receptor
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INTRODUCTION |
Long-term potentiation (LTP) of
synaptic efficacy is widely regarded as a putative long-term memory
mechanism. This is based in part on the reported persistence of LTP
over time in freely behaving animals. Evidence to date, however,
indicates that although LTP in the dentate gyrus can last from a few
days to many weeks, it does not persist stably enough to support very
long-term memories lasting months or longer (Racine et al., 1983 ;
Abraham and Otani, 1991). Although these findings are consistent with
theoretical and empirical evidence that the hippocampus functions as a
temporary memory store (Marr, 1971; Milner, 1989; Squire, 1992), there
is growing evidence that, in fact, the hippocampus may have the
capacity for more permanent information storage (Nadel and Moscovitch, 1997). The question remains, therefore, whether LTP in the hippocampus is necessarily decremental or whether it can be maintained stably under
some conditions. Although it has been shown previously that theta-burst
stimulation in area CA1 can induce LTP that is stably maintained over
several weeks (Staubli and Lynch, 1987), it cannot be determined from
these data whether the LTP would have been maintained over months.
A complicating factor in the investigation of the inherent stability of
induced LTP is its sensitivity to behavioral variables after the period
of induction. In two studies, it has been shown that exposure to a
mildly stressful novel environment (Xu et al., 1998) or novel stimulus
(Manahan-Vaughan and Braunewell, 1999) shortly after the induction of
LTP in CA1 will cause a rapid and persistent reversal of the LTP.
Interestingly, the novel experiences were effective at reversing LTP
when given 1 hr, but not 24 hr, after induction, indicating that the
experiences interfered with the initial consolidation but not the
maintenance of LTP. It is not clear from these studies, however,
whether the novel experience was itself sufficient to reverse LTP, or
whether the low-frequency stimulation given simultaneously was also required.
We have revisited the issue of LTP persistence in the dentate gyrus
region of the hippocampus and found that LTP can indeed show longevity
appropriate for a mechanism underlying memory storage lasting months or
longer. We also found that such stable LTP is nonetheless profoundly
sensitive to experience and can be reversed after exposure to enriched
environments in the weeks after LTP induction. However, stable LTP
appeared to eventually consolidate and become resistant to
experience-induced decay.
Portions of these data have been published previously in preliminary
form (Abraham et al., 2001).
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MATERIALS AND METHODS |
Surgery. Adult male Sprague Dawley rats (350-500 gm)
were anesthetized with sodium pentobarbital (60 mg/kg, i.p.). Following standard stereotaxic surgical procedures, stimulating and recording stainless steel wire electrodes, insulated except for the cut tip, were
implanted bilaterally to establish perforant path-evoked field
potentials recorded in the dentate hilus, as described previously (Abraham et al., 1993). The initial slope of the field EPSPs
(fEPSPs) was used as the measure of synaptic efficacy. After surgery,
animals were housed individually in small standard cages and exposed to a normal 12 hr light/dark cycle.
Electrophysiology. Beginning 2 weeks after surgery, animals
were taken to a recording room and tested for usable recordings (fEPSP
slope  3.5 mV/msec at stimulus currents  500 µA). If the recordings
met these criteria, baseline testing (0.05-0.017 Hz, 150 µsec pulse
duration, alternating between the two hemispheres for 20-30 min) was
undertaken, using a stimulus strength that elicited a 2-4 mV
population spike. Baseline recordings were made at the same time of day
(during the animal's light cycle) two to three times per week until a
stable level of evoked responses was obtained for at least four
consecutive sessions, i.e., the responses varied by less than ±5%.
The responses from these sessions were then used to calculate an
average baseline response. On the day of LTP induction, high-frequency
stimulation (HFS) was delivered after a 30 min baseline recording
period, and responses were followed for another 60 min. Recording
sessions were generally conducted on days 1, 2, 3, 4, and 7 after
tetanus (or else days 1, 3, 5, and 7 after tetanus) and two times per
week thereafter. The level of LTP on these days was calculated as the
percentage fEPSP increase (averaged over the last half of the recording
session when responses are stable) relative to the baseline average
response, as is our standard procedure (Abraham et al., 1993, 1994).
The responses early in a recording session are somewhat variable
because of the effects of handling and animal transfer to the recording
chamber. LTP on the day of tetanization, however, was calculated
relative to the average fEPSP recorded over the 15 min before tetanus. Similarly, the percentage changes for the control nontetanized hemisphere fEPSPs were calculated relative to their own average baseline value.
HFS protocols. On the day of tetanization, HFS was applied
to the perforant path in one hemisphere using 400 Hz, 25 msec trains (at the baseline stimulus current intensity but with the pulse duration
increased to 250 µsec). The nontetanized hemisphere served as a
control for changes in an animal's arousal and hormonal state, and
experiences over time, age, activity levels, etc. Trains were delivered
in sets of five trains, with 1 sec between trains and either 1 or 10 min between sets. The number of sets of HFS trains delivered per animal
varied across groups. The hippocampal electroencephalogram was
displayed on an oscilloscope during HFS to monitor for epileptiform afterdischarges, but none were observed in this study (although such
abnormal activity is often seen after HFS given to area CA1, indicating
that this method is capable of detecting afterdischarges.)
In four animals, stimulating electrodes were placed separately in the
medial and lateral perforant pathways according to previous protocols
(Abraham et al., 1994). Baseline recordings were made for the lateral
path before and after HFS as described above. During HFS,
near-simultaneous tetanization was delivered to both the medial and
lateral perforant paths, with each lateral path stimulus preceding each
medial path stimulus by 5 msec. No control hemisphere recordings were
made in these animals for technical reasons.
Data analysis. LTP was defined as an fEPSP increase 15%
measured 60 min post-HFS. In animals in which the criterion was not met, the LTP was classified as decremental; in those in which the
criterion was met, LTP maintenance was analyzed further. First, the
fEPSP measurements made in the tetanized hemisphere were adjusted for
variations in the recordings of the control hemisphere, where available, by subtracting the percentage changes in the control hemisphere fEPSPs from the those in the tetanized hemispheres. Single
three-parameter negative exponential curves were then fitted to the LTP
maintenance data, beginning on day 1 post-HFS, without being
constrained as to the final baseline level or the slope of the
function. The equation used was y = y0 + ae( bt), where
y0 is the exponential asymptote,
a is a value that gives the y intercept when
added to the asymptote, b is the rate of exponential decay,
and t is the time after LTP induction in days. The reported
decay time constant ( ) is the inverse of the decay rate parameter
b and is the time taken for the function to decline by 63%.
Stable LTP was defined as a dataset for which the exponential asymptote
was 10% above baseline, and the recordings were maintained for at
least 42 d after tetanus. It should be noted that only ~50% of
the animals had usable recordings in the control hemisphere. However,
stable LTP was identifiable in both raw and corrected datasets,
indicating that correction for control recordings was not necessary for
its identification. A few animals showed marked, precipitous changes in
the recordings from one or both hemispheres beginning at random times
after tetanus. In these cases, the wave-shapes also changed in a way
characteristic of a significant movement of the recording electrode
position, such as the development of a late negativity in the waveform
or even a complete reversal of the positive-going waveform into a
negative-going waveform. Where such events occurred in the tetanized
hemisphere, the exponential asymptotes for the tetanized hemispheres in
these animals were more negative than  50%. Accordingly, all data
from these animals (n = 4) were discarded, unless
specified otherwise.
Immunohistochemistry and densitometry. Animals were
killed by overdose with halothane at defined times after
tetanization, and the brains were removed, frozen on dry ice, and
stored at 70°. Coronal sections (16 µm) through the dorsal
hippocampus were thaw-mounted onto
poly-L-lysine-coated glass slides.
Immunohistochemical staining with an antibody to
serine-133-phospho-cAMP response element-binding protein (pCREB) (UBI;
1:500 dilution) was performed as described previously (Butterworth and
Dragunow, 1996), with minor changes. Endogenous peroxidase activity was
blocked by incubation in
H2O2 (1% in 50% methanol,
5 min), and all PBS solutions contained 0.2% Triton X-100.
Densitometric analysis was performed on blinded sections at 125×
magnification using MD30plus software (Leading Edge). For each
section, staining densities for the entire dentate granule cell layer
were normalized to background staining, which was measured bilaterally
in the stratum radiatum in a camera field (1 mm width) immediately
medial to a vertical line through the lateral end of the dentate gyrus
lower blade. Densitometry measurements were corrected for light source
and camera drift. Data were pooled for two to three sections from each brain.
Enriched environment. Animals in the enriched environment
(EE) group were housed individually in standard cages but periodically were placed in groups of two to three in a large (70 × 100 × 40 cm) fiberglass box containing novel objects, drinking water,
normal lab chow, and Kellogg's Cocoa Pops scattered throughout the
chamber. The box was in a room different from the vivarium and the
recording room. The arrangement of objects was varied daily. The rats
were placed in the enriched environment for either 1 hr/d for 21 d during the light cycle or overnight for 14 hr (including the entire 12 hr dark cycle) for 7 d. When electrophysiological recordings were
made, these occurred 3-4 hr before placement in the enriched environment for that day. Animals in the home cage control group (HC)
remained unhandled in the vivarium, except during electrophysiological recordings and routine cage cleaning. Exposure to the enriched environment generally had little effect on fEPSPs in the control hemisphere, although transient elevations of the population spike were
noted during the period of EE treatment (Irvine and Abraham, 2001).
Thus exposure to EE by itself did not produce any net LTP or long-term
depression (LTD) effects, although EE may have caused LTP and LTD at
different synapses such that there was no net change in overall
synaptic efficacy, as detected by field potential recordings.
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RESULTS |
Stable LTP can be induced in the dentate gyrus, depending on the
stimulus protocol
The experiments were conducted while the rats were quietly
awake. Before tetanization, there were no significant
differences between HFS groups in either the baseline EPSP slope or
population spike amplitude (one-way ANOVA; p > 0.4)
(Table 1). When five trains of HFS (5T)
were administered, a moderate LTP was induced on average (15 ± 5%; n = 6) (Fig.
1A). Two animals did
not reach LTP criterion (15% change), and in the remaining four
cases the LTP decayed rapidly to baseline levels within 48 hr (mean
= 0.7 d). Twenty trains of HFS (20T) induced more robust
LTP (30 ± 3%; n = 6) (Fig. 1A). In accord with
our previous findings (Abraham et al., 1993), this LTP also decayed to
baseline for five of six animals, with an average decay time constant
of 1.0 d as determined by fitted exponential functions. For one
animal, however, the LTP did not decay but stabilized unexpectedly at
an asymptotic level of 23% LTP that lasted at least 77 d, the
longest it was tested. To formally categorize such stable LTP, we
adopted the stringent criteria that the LTP must have been recorded for
at least 42 d post-HFS and that the asymptote of the negative
exponential function fitted to the post-HFS LTP values was 10% above
baseline. LTP that did not meet these criteria for stability was
classified as decremental.
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Figure 1.
Protocol dependence of stable LTP in the dentate
gyrus. A, LTP induction by different 400 Hz HFS
protocols. All protocols induced a significant LTP
(p < 0.05), measured 55-60 min post-HFS,
that was not statistically significantly different between groups
(one-way ANOVA; p > 0.1). 5T,
20T, and 50T indicate the total number of
400 Hz tetanic trains, delivered as sets of five trains, 1 min apart.
4*5T, Four sets of five trains delivered 10 min apart.
Data are mean ± SEM. B, Summary histogram
illustrating the percentage of animals showing stable LTP in the
dentate gyrus for each protocol used. Both the pattern and number of
stimulus trains affected the probability of stable LTP occurrence.
5T, Zero of 6 animals; 20T, 1 of 6;
4*5T, 3 of 6; 50T, 8 of 12. C, Decremental LTP for one animal given 4*5T
(arrow). Data for both tetanized ( ) and control ( )
pathways are plotted. Average baseline value is represented by the
dotted line. Insets are the rising phases
of the fEPSPs (averages of 10 responses) before population spike onset
and recorded from the tetanized hemisphere at the times indicated
relative to HFS. Calibration: 2 mV, 0.5 msec. D, Stable
LTP for one animal given 50T. Data for both tetanized () and control
() pathways are plotted. Inset waveforms as in
C. The data for the tetanized hemispheres in
C and D have not been corrected for the
control hemisphere changes.
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To find more reliable methods of generating stable LTP in the dentate
gyrus, two additional tetanization paradigms were used. First, the 20T
HFS was altered by separating the four sets of five trains by 10 min
(4*5T), instead of the standard 1 min, because previous studies have
shown that the delivery of stimulus trains spaced over time can prolong
the duration of synaptic plasticity (Huang and Kandel, 1994). Using
this protocol, robust LTP was again obtained (29 ± 4%;
n = 6) (Fig. 1A), and three of six
animals met the criteria for stable LTP (Fig. 1B),
with an average asymptotic level of 24% LTP. The remaining three
animals showed rapid LTP decay, with an average time constant of
3.3 d (Fig. 1C). In the second paradigm, 50 trains
(50T) were delivered using our standard pattern of massed trains (1 min
between sets of five trains). Once again, robust LTP was generally
induced (25 ± 5%; n = 12) (Fig.
1A), although in this condition three animals showed
<15% initial potentiation. Remarkably, however, 8 of 12 animals met the criteria for stable LTP, with an average asymptote of 20% LTP
(Fig. 1B,D).
The frequency of stable LTP occurrence varied significantly between the
four HFS groups ( 2 = 9.17;
p < 0.05) (Fig. 1B). This suggests
that the apparent stability of LTP was not caused by a random upward
instability of the responses but rather by the pattern and number of
stimulus trains used to induce the LTP. However, it is important to
consider whether the apparently stable LTP was caused by some aspect of our experimental or analysis procedures. First, it is possible that
these data were biased by the fact that the data for four animals were
discarded because of major response changes that developed at a random
time after tetanus in one or both hemispheres. However, these four
animals were relatively evenly represented across the groups (20T,
n = 1; 4*5T, n = 2; 50T,
n = 1). Furthermore, even if these animals were
categorized as showing decremental LTP and included in the
2 analysis, there was still a
significant difference in the occurrence of stable LTP across groups
(2 = 8.87; p < 0.05).
Second, it is possible that the procedure of correcting for control
hemisphere changes could have made a decremental LTP appear as stable
LTP, if both the control and potentiated responses were gradually
declining equally over time. To assess this possibility, exponential
fits were applied only to the data from the tetanized hemispheres to
assess LTP stability. This resulted in changing the categorization of
four animals: LTP in two animals changed from stable to decremental
(one each in the 4*5T and 20T groups), and the reverse was true in two
other animals (1 each in the 4*5T and 20T groups). This left the
frequency of stable LTP across groups unchanged, and thus
2 analysis continued to show a
significant difference between groups. Finally, we considered whether
the number of days or baseline recording sessions between surgery and
tetanization could account for the group differences in the stability
of LTP. A one-way ANOVA revealed no significant difference between
groups in the time between surgery and tetanus
(p > 0.4) (Table 1). In contrast, there was a
significant group difference in the number of baseline recording
sessions before tetanus (F(3,30) = 3.14; p < 0.05). However, this was not related to LTP
stability because post hoc Student's-Newman-Keuls
pairwise comparisons revealed that the only significant differences
were between the 5T group on the one hand and the 20T and 4*5T groups
on the other (Table 1). The 50T group, with the highest frequency of
stable LTP occurrence, did not differ on this measure from any of the
other three groups. Taking all of these additional analyses together,
we conclude that LTP stability was not an artifact of discarding
animals from the study, the amount of handling and recording before
tetanus, variations in electrophysiological parameters before tetanus, or the use of control hemisphere data for correction purposes.
To compare the temporal profile of maintenance between stable and
decremental LTP, the data from animals receiving 20 or more trains were
pooled according to their LTP classification (Fig. 2A). For this
comparison, we also selected only those animals showing 15% initial
LTP, so that there was a nearly identical degree of LTP measured 60 min
post-HFS for the two groups (stable LTP: 30 ± 3%,
n = 12; decremental LTP: 31 ± 3%,
n = 9). Despite the concordance of LTP induction, the
differential maintenance of LTP is striking. The average asymptote from
the fitted exponential functions for the stable LTP group was 21 ± 3% LTP, compared with 0.4 ± 1% LTP for the decremental LTP
group (Fig. 2A). For the stable LTP group, the
average period of time post-HFS over which recordings were made before
the recordings were terminated was 68 d, with a range of 42-119
d. Importantly, recordings made in the control hemispheres over the
same period of time remained stable, indicating that neither the stable
nor decremental LTP was caused by chronic changes in animal physiology,
movement, hormonal status, age, or similar whole-animal variables (Fig. 2A) (n = 9; collapsed across type of
LTP).
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Figure 2.
Maintenance of stable LTP. A,
Summary LTP persistence plot for animals receiving 20 or more stimulus
trains and exhibiting >15% LTP, divided into two groups on the basis
of whether the criteria for stable LTP were met (,
n = 12) or not (i.e., LTP was decremental) (,
n = 9). Data represent mean ± SEM, corrected
for control pathway changes. The available control hemisphere data,
combined across the two groups, are also plotted ( ;
n = 9). Note the relative stability of the control
hemisphere recordings. B, Stable LTP lasting 1 year
post-HFS for an individual animal. Data are from the tetanized
hemisphere, corrected for control pathway values that declined by
~5% during the recording period. Solid curve is the
fitted negative exponential function, with asymptote
(a) of 10% LTP and decay time constant of 127 d.
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In one animal, the recordings were extended from the 119 d used in
the above analysis to 1 year post-HFS (369 d) (Fig.
2B). The asymptote for the fitted exponential
function fell only slightly during this time, from 13% for the
119 d function to 10% for the 369 d function, illustrating
that LTP in perforant path-dentate gyrus synapses can be remarkably
enduring, extending across a significant portion of a rodent's
lifespan. The slight reduction in the fitted asymptote, however, may be
indicative of a slow decay of the LTP over time.
Induction of stable LTP in lateral perforant path synapses
Up to this point, the experiments involved electrical stimulation
in the angular bundle that activated a mixture of medial and lateral
path fibers, but principally those from the medial perforant path as
determined by the electrophysiological properties of the responses. To
determine whether lateral path synapses can also exhibit stable LTP, we
implanted animals with separate stimulating electrodes in the medial
and lateral aspects of the angular bundle. This allowed us to
independently activate the lateral path before and after HFS (Abraham
et al., 1994). During tetanization, the medial and lateral paths were
coactivated using the 50T protocol to ensure a robust initial LTP in
the lateral path, because we have found previously that the lateral
path exhibits a relatively modest, rapidly decaying LTP when activated
alone (Abraham et al., 1994). Using the combined tetanization protocol,
we observed stable LTP lasting >100 d in three of four animals, with
an average exponential asymptote of 21 ± 4% in the three animals
showing stable LTP (Fig. 3).
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Figure 3.
Induction of stable LTP in the lateral perforant
path. Plotted are the average lateral path data for three animals that
showed stable LTP after 50T HFS, simultaneously to both medial and
lateral paths (arrow). Data have not been corrected
because no control hemisphere recordings were made. Solid
curve is the fitted negative exponential function for the
average plot, with a time constant of 42 d and an asymptote of
24% LTP (a value very similar to the 21% asymptote obtained by
averaging the asymptotes obtained for each individual animal). A fourth
animal exhibited long-lasting but decremental LTP (data not shown).
Waveforms are lateral path response averages of 30 sweeps taken just
before tetanization (pre), and on days 21 (d21), 63 (d63), and 101 (d101) post-HFS, for a representative animal.
Calibration: 2 mV, 5 msec. Inset diagram depicts the
placement of stimulating electrodes separately in the lateral
(lpp) and medial (mpp) perforant paths,
plus a recording electrode in the dentate hilus, below the granule cell
(gc) layer of the dorsal blade.
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Sensitivity of stable LTP to variables on the day
of tetanization
It was curious that 50 HFS trains (activating primarily medial
path fibers) induced stable LTP in the present experiments, whereas we
had routinely observed only decremental LTP using this same paradigm in
previous studies (Abraham et al., 1993, 1995). Careful analysis of the
relevant stimulus protocols revealed only one significant
methodological difference. In the present experiments, recordings to
test pulse stimulation were made for 30 min before and 60 min after the
HFS, whereas previously we had used only 10 min and 20-30 min baseline
recording periods, respectively (Fig.
4A). All of the
tetanization parameters were otherwise identical. Indeed, it is
noteworthy that many other previous studies using relatively short
baselines also found dentate LTP to be decremental (Racine et al.,
1983; Bloch and Laroche, 1985; de Jonge and Racine, 1985). To confirm
that the length of the baseline recordings on the day of tetanization
was a crucial protocol difference, three additional animals were given
the short-baseline 50T paradigm. All three animals showed decremental
LTP, with an average time constant of 32 d, well within the range
of our published findings for this protocol (Abraham and Otani, 1991;
Abraham et al., 1993, 1995). The present data and the data from Abraham
et al. (1995) are shown in combined form in Figure 4B
to illustrate the difference in LTP stability between the two types of
50T protocols. A two-way ANOVA with repeated measures on one factor
revealed that there was a significant time × group interaction
(F(9,171) = 4.55; p < 0.001) and thus a faster decay over time for the short-baseline condition. This conclusion is supported by the fact that the frequency of occurrence of stable LTP for the short-baseline treatment (1 of 9 animals) was significantly less than that observed with the longer
baseline protocol (8 of 12 animals; 2 = 6.48; p < 0.05), although the levels of initial LTP
induction were virtually identical. We tentatively interpret this
difference in results as arising from the difference in the time of
animal handling and transfer between the recording chamber and home
cage, relative to the time of HFS. Although these procedures were
highly practiced, the minor stress or stimulus during such handling
close to the time of LTP induction in the short-baseline condition may have interfered with LTP stability. This has been shown previously for
LTP in area CA1 (Xu et al., 1998; Manahan-Vaughan and Braunewell, 1999). We cannot rule out the possibility, however, that the difference in the numbers of test pulses delivered before and after the HFS may
have contributed to the group differences in LTP stability.
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Figure 4.
Summary LTP persistence plots for animals
receiving 50T. A, Diagram of the timing of test-pulse
recording periods (and time spent in the recording chamber) and the
delivery of 50T HFS for the short- and long-baseline conditions. The
50T HFS took 10 min to complete. B, Animals given 50T
with the long-baseline protocol (30 and 60 min test-pulse periods
before and after LTP, respectively; n = 12)
generally showed stable LTP. Animals given short test-pulse periods of
10 and 20 min, respectively, showed decremental LTP for the same
tetanization protocol (n = 9). The plotted data for
the latter group (mean ± SEM; corrected for control pathway
values) represent a combination of three animals studied in the present
experiment plus six animals that received the identical protocol and
were reported by Abraham et al. (1995). The maintenance of LTP was
statistically different between the long- and short-baseline groups
(see Results). C, pCREB immunoreactivity in the dentate
granule layer at 2 hr after the 50 train long-baseline protocol,
compared with the immunoreactivity found in the nontetanized hemisphere
of the same animal. Scale bar, 0.5 mm.
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Relation of stable LTP to CREB phosphorylation
There is considerable evidence across a number of species that the
persistence of LTP and the establishment of long-term memory are linked
by their dependence on the phosphorylation of the transcription factor
CREB at serine-133 (Bourtchuladze et al., 1994; Yin et al., 1995;
Schulz et al., 1999; Davis et al., 2000). To investigate whether the
protocol that is efficient at inducing stable LTP is also distinguished
by its ability to induce CREB phosphorylation (pCREB), new groups of
animals, treated identically as above for the study of LTP persistence,
were killed at 2 or 4 hr after the two 50T protocols and processed for
pCREB immunohistochemistry using a ser133-pCREB antibody.
Delivery of the long-baseline 50T protocol produced a reliable increase
in pCREB immunoreactivity relative to the control nontetanized
hemisphere at 2 hr post-HFS (three of three animals) (Fig.
4C). Quantitative image analysis revealed this effect to be
significantly greater than the response following the short-baseline
50T protocol (long baseline: 23 ± 8%; short baseline: 1 ± 6%; Mann-Whitney U test; p = 0.05).
However, the effect was transient because there was no difference
between groups in pCREB immunoreactivity at 4 hr post-HFS
(n = 4 both groups; Mann-Whitney U test;
p = 0.1; data not shown). Administration of the
NMDA receptor antagonist
(RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid
(CPP; 10 mg/kg, i.p.) blocked the induction of LTP by the 50T
long-baseline protocol (5 ± 2%; n = 4;
p > 0.1), demonstrating the NMDA receptor dependence
of stable LTP. CPP also significantly reduced the increase in pCREB
immunoreactivity relative to the non-CPP-treated animals (Mann-Whitney
U test; p = 0.02), although a small but
statistically significant increase in immunoreactivity still occurred
relative to the control hemisphere in the CPP-treated animals (10 ± 2%; n = 4; paired t test;
p < 0.05).
Reversal of stable LTP by repeated exposure to an
enriched environment
The stability of hippocampal LTP demonstrated above is remarkable
given the classical view of the hippocampus as a temporary memory store
(Marr, 1971; Milner, 1989; Squire, 1992). The stability of LTP may
reflect, however, the fact that in our experiments the animals lived in
an impoverished environment (single housing in small cages) without the
opportunity for additional learning experiences that could compete or
interfere with the newly established changes in synaptic weights, as
may occur for animals living in a more naturalistic and changeable
environment. To test this possibility, two groups of five animals were
matched for standard perforant-path LTP induction and persistence over
14 d after long-baseline 50T HFS, using the criteria that the
initial LTP was 15%, the asymptote of the fitted negative
exponential function over 14 d was >10%, and the LTP value on
day 14 post-HFS was 10%. One group (EE) was then placed in an
enriched environment for 1 hr/d for 3 weeks. The novel environment
provided the animals with many sources of information and opportunities
for learning, including extra handling, a novel room, a novel and
larger holding box, novel objects, social interaction, and increased
motor activity. The animals in the other group were kept in their home
cage (HC), except when tested electrophysiologically. As shown in
Figure 5A, the HC group
exhibited the expected development of stable LTP (average
asymptote = 13% LTP). In contrast, the LTP in the EE group
gradually declined over the period of enrichment and remained
significantly below the level of the HC group even after exposure to
the novel environment was terminated (two-way ANOVA with repeated
measures over days 7-45 post-HFS; group × time interaction
F(11,88) = 3.46; p < 0.001). The response decay represents a depotentiation effect because it was specific to the potentiated hemisphere in the EE group. The
responses in the control hemispheres of the same animals were little
affected (Fig. 5A), apart from transient elevations of the
population spike (data not shown).
View larger version (38K):
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|
Figure 5.
Time-dependent reversal of stable LTP by
exposure to enriched environments. A, Comparison of LTP
maintenance for two groups: home cage controls (HC;
n = 5) and animals receiving EE exposure for 1 hr/d
for 3 weeks (EE; n = 5). The EE
group showed a lasting reversal of LTP. Data are corrected for changes
in the control hemisphere that have also been plotted for the EE group
(n = 4). Smooth curve is the fitted
negative exponential function to the HC data; asymptote = 13%
LTP. B, Exposure of a separate EE group
(n = 5) to the enriched environment overnight for
7 d led to a more rapid and robust reversal of LTP maintenance,
compared with a new HC group (n = 6). Because of
equipment malfunction, recordings were not made in two EE animals
beyond 3 d after EE treatment. Data are corrected for changes in
the control hemisphere that are also plotted for the EE group
(n = 5). Smooth curve is the fitted
negative exponential function to the HC data; asymptote = 18%
LTP. C, Input-output curves for the EE group presented
in B. fEPSP slopes were measured across 15 stimulus
strengths (10-600 µA) and expressed as a percentage of the maximal
response obtained pre-HFS. The data (uncorrected) were obtained at
three time points: pre-HFS, 14 d post-HFS
(pre-EE), and 21 d post-HFS
(post-EE). EE exposure significantly reversed LTP
across all stimulus strengths (F(2,6) = 7.30; p < 0.05). Inset waveforms
are averages of 10 responses recorded during the same sessions as
the input-output curves for a single animal in the EE group.
Illustrated are the rising phase of the fEPSP before population spike
onset for a single animal. Calibration: 3 mV, 0.5 msec.
D, Overnight EE exposure failed to reverse LTP when
given ~90 d post-HFS (range 85-103 d; n = 6).
For convenience, data (corrected for control hemisphere changes) have
been aligned for each animal relative to the start and finish of EE
exposure. All six animals received EE exposure for 1 week, and three of
these animals were given EE exposure for 2 further weeks. LTP for all
six animals was monitored for a further 17 d after EE
treatment.
|
|
In an attempt to induce a more robust LTP reversal, the "dose" of
environmental enrichment was increased by giving a new set of animals
overnight access (14 hr/d) to the enriched environment for a 7 d
period, again beginning 14 d post-HFS. Indeed, this treatment
produced a more rapid and dramatic reversal of LTP (n = 5), as compared with a new matched set of HC controls
(n = 6), which again showed stable LTP with an average
asymptote of 18% LTP (Fig. 5B). The two groups showed
statistically different levels of LTP, as indicated by a
repeated-measures ANOVA over days 7-24 post-HFS (group × time
interaction F(5,40) = 5.87;
p < 0.001). Input-output analysis revealed that the
reversal of LTP occurred equivalently across a range of stimulus
strengths (Fig. 5C). Finally, to determine whether the
reversibility of LTP was time-dependent, six animals showing stable LTP
for ~90 d (range = 85-103 d; n = 6) were
subsequently given overnight exposure to the enriched environment for
either 7 (n = 3) or 21 d (n = 3).
Although this treatment increased the variability of the responses
somewhat, it did not change the average degree of LTP expressed either
during or after the period of exposure to the enriched environment
(average LTP just before EE: 16 ± 6%; just after EE: 20 ± 7%) (Fig. 5D).
| |
DISCUSSION |
The hippocampus and associated medial temporal lobe structures are
believed by many theorists to serve as a holding store for mnemonic
information, while contributing to the gradual integration of the newly
learned information into the memory structures of the neocortex (Teyler
and Discenna, 1985; McClelland et al., 1995; Eichenbaum et al., 1996;
Rolls, 1996). Accordingly, it has been suggested that
learning-associated synaptic plasticity should be rapidly but
transiently induced in the hippocampus, whereas plasticity in the
neocortex would require repeated activation episodes, with small but
stable increments of synaptic change in response to each episode
(Milner, 1989; McClelland et al., 1995). On the whole, previous data
describing the decremental nature of LTP in the dentate gyrus region of
hippocampus have been in accord with this view (Racine et al., 1983;
Abraham and Otani, 1991). However, Staubli and Lynch (1987) reported
that stable (nondecremental) LTP lasting 1-5 weeks could be induced by
theta-burst stimulation in area CA1, and Bliss and Gardner-Medwin (1973) reported a case of stable maintenance of LTP in rabbit dentate
gyrus over many weeks. Here we have revisited this issue for the
dentate gyrus and found that this hippocampal subregion indeed has the
capacity for stable LTP. Thus, we were able to observe stable LTP
lasting months for both medial and lateral perforant path synapses, and
in one case lasting up to 1 year, a significant proportion of a
rodent's lifespan. Importantly, we used exponential curve-fits
for data from individual animals to provide a quantitative measure of
stability. This proved useful, in part, because the LTP often underwent
a period of slow decline before reaching its apparent asymptotic level.
The present demonstration of very long-term stability of LTP indicates
that LTP does indeed have the capacity, after a single induction
episode, to underlie memory storage across months or more. Although it
is vital to know whether LTP has this capacity, it is
nonetheless unknown whether real world memory mechanisms require such
stable plasticity because, for example, occasional periods of memory
retrieval and rehearsal could restrengthen any underlying synaptic
plasticity before it decays completely.
What are the implications of stable LTP for our understanding of
hippocampal function? Long-term maintenance of LTP appears to challenge
the conventional wisdom that the hippocampus is a temporary memory
store. It is consistent, however, with recent controversial suggestions
from clinical cases (showing prolonged retrograde amnesia after
hippocampal damage) that this brain region may be involved more
directly in long-term memory storage than previously supposed (Nadel
and Moscovitch, 1997; Cipolotti et al., 2000). In rats, the long-term
storage of information in the hippocampus might support both the
establishment (Kentros et al., 1998) and the long-term stability of the
place fields of hippocampal neurons (Thompson and Best, 1990; Lever et
al., 2002) or aid the generation and updating of stable spatial
reference frames that may be important for animal navigation
(McNaughton et al., 1996). It may be, however, that such
interpretations are valid only for animals living in a stimulus-poor
environment, because we observed that otherwise stable LTP rapidly
decayed after repeated novel experiences. Thus for animals living in a
naturalistic and changing environment, LTP (and perhaps memory storage)
in the hippocampus may normally be short-lasting, in accord with the
above-mentioned prevailing views of hippocampal function.
The reversal of LTP could be attributable to any number of behavioral
variables associated with experiences in the enriched environment. It
seems likely, however, that extra information processing in the dentate
gyrus was somehow responsible for resetting the weights of the
perforant path synapses. Such resetting was presumably caused by a
homosynaptic long-term depression or depotentiation effect, because it
occurred for the potentiated synaptic responses but not for the control
responses recorded in the opposite hemisphere of the same animals.
Whatever the mechanism, the reversal of LTP may represent a synaptic
mechanism underlying the psychological phenomenon of retrograde
interference, whereby newly learned information interferes with the
retrieval of previously learned information.
Our findings differ from previous studies of LTP reversal by novel
experience, which were conducted in CA1 and had a narrow time window of
effect spanning only several hours after LTP induction (Xu et al.,
1998; Manahan-Vaughan and Braunewell, 1999). In contrast, we observed
that repeated exposure to enriched environments reversed LTP even when
commencing 14 d after induction. Thus, the mechanism of LTP
disruption may differ between the two sets of studies. Nonetheless, we
did find that stable LTP had a consolidation phase, because it
eventually became resistant to reversal by enrichment by 3 months after
induction. This finding is thus consistent with the recent observation
that hippocampus-dependent memory also consolidates across weeks after
initial training (Shimizu et al., 2000). This prolonged consolidation
of memory was dependent on NMDA receptor activation during the
consolidation period. Whether LTP consolidation is also NMDA receptor
dependent remains to be investigated.
Previous experiments using post-training novel environments have
produced conflicting effects on the retention of hippocampus-dependent memory. On the one hand, exposure to a novel open field inhibited retention of inhibitory avoidance performance acquired 1 hr previously (Viola et al., 2000). On the other hand, post-training exposure to an
enriched environment for 2 weeks facilitated retention of contextual
fear conditioning (Feng et al., 2001). The former study is consistent
with the studies showing a particular sensitivity of LTP to reversal
early after its induction (Xu et al., 1998; Manahan-Vaughan and
Braunewell, 1999). The latter study, however, appears to contrast
directly with the present one, because we observed that new behavioral
experiences caused a reversal of a synaptic memory trace (i.e.,
LTP). These findings of Feng et al. (2001) and the present study are
not necessarily contradictory, however, and we propose the following
solution to the apparent paradox. Exposure to an enriched environment
facilitates memory retention (Feng et al., 2001) because it facilitates
longer-term storage in the neocortex. At the same time, it promotes
erasure of the memory trace in the hippocampus, as exemplified by the reversal of LTP in our experiments, to facilitate new learning. This
hypothesis can be tested experimentally, because it predicts that the
retrograde amnesia gradient resulting from hippocampal damage will be
shortened for animals exposed to an enriched environment after
training, because of more rapid consolidation in other structures.
In the present experiments, the induction of stable LTP was associated
with the phosphorylation of CREB, which may play a role in
signaling gene expression critical for LTP maintenance. Our findings
thus support previous studies demonstrating that hippocampal LTP
protocols can cause increases in pCREB and CRE-mediated gene expression
that are dependent only partially on NMDA receptor activation (Impey et
al., 1996) and are associated with the late phase of LTP (Bourtchuladze
et al., 1994; Schulz et al., 1999; Davis et al., 2000). We have
extended these findings for dentate LTP, however, by showing that pCREB
is particularly associated with protocols that induce stable LTP
lasting months, whereas LTP that is long-lasting but nonetheless
decremental can occur independently of raised pCREB levels (Walton et
al., 1999). We tentatively attribute the failure of the short-baseline
HFS protocol to readily induce either pCREB or stable LTP to the
behavioral disruption accompanying the removal of the animals from the
recording chamber to their home cage. This is consistent with the
demonstration that both training-induced pCREB expression in the
hippocampus and long-term memory formation are inhibited in a
time-dependent manner by exposure of the animals to a mild stressor
(i.e., a novel environment) after the learning experience (Viola et
al., 2000). It should be noted, however, that the duration of LTP
maintenance is likely regulated by a host of transcription factors in
addition to pCREB, as well as by other genes coding for cytoplasmic
proteins (Abraham et al., 1993; Jones et al., 2001), and the
persistence of LTP can vary dramatically (Abraham and Otani, 1991;
present results). Thus the late phase of LTP in vivo may not
be a unitary phenomenon and may depend instead on the complement and
pattern of expression of the different signaling molecules induced by a
stimulation protocol or learning experience.
In summary, we have addressed one of the key issues regarding LTP,
namely, whether it can in principle be maintained long enough to serve
as a mechanism underlying stable long-term memory. Our data indicate
that hippocampal LTP in adult animals does indeed have this capacity.
Furthermore, if the LTP survives intact over the first few weeks after
its induction, it then becomes resistant to further change and in
principle may contribute either to very long-term memory storage or to
a very long-term change in the way that new information is processed
during subsequent experience. This may apply only to animals living in
stimulus-poor environments, however. Under naturalistic conditions, LTP
in the hippocampus appears to be readily overwritten as a result of new
experiences, in accordance with conventional theories of hippocampal
function. It remains to be investigated whether LTP is both stable and
resistant to reversal in other structures, such as the neocortex, that
are believed to be responsible for permanent memory storage.
| |
FOOTNOTES |
Received June 14, 2002; revised Aug. 8, 2002; accepted Aug. 22, 2002.
This research was supported by grants from the New Zealand Health
Research Council and the New Zealand Marsden Fund. We thank Assoc.
Prof. D. Bilkey, Dr. D. Ireland, Dr. B. Mockett, Assoc. Prof. J. Wickens, and Dr. A. Heynen for comments on previous versions of this
manuscript, and P. Curtis and S. O'Carroll for excellent technical assistance.
Correspondence should be addressed to Prof. Wickliffe C. Abraham,
Department of Psychology, University of Otago, Box 56, Dunedin, New
Zealand. E-mail: cabraham{at}psy.otago.ac.nz.
| |
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TOP
ABSTRACT
INTRODUCTION
