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 Previous Article
The Journal of Neuroscience, October 1, 1999, 19(19):8712-8719
Time-Dependent Reversal of Long-Term Potentiation in Area CA1 of
the Freely Moving Rat Induced by Theta Pulse Stimulation
Ursula
Stäubli and
Joey
Scafidi
Center for Neural Science, New York University, New York, New York
10003
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ABSTRACT |
Previous studies in slices have shown that low-frequency
stimulation at 5 Hz, i.e., theta pulse stimulation (TPS), completely reverses long-term potentiation (LTP) in area CA1 when delivered within
1-2 min after induction but produces progressively less depotentiation
at longer delays, until it has no longer any impact at 30 min after
induction. The present study examined whether LTP in the freely moving
rat exhibits a similar time-dependent susceptibility to reversal. Adult
male Long-Evans rats with bilateral stimulating electrodes activating
collateral/commissural projections to area CA1 were used. A 1 min
episode of TPS, ineffective when applied to naive pathways, was found
to permanently erase LTP when delivered to the test pathway either 30 sec or 15 min after induction. Administered at a delay of 30 min,
however, the same treatment no longer had any impact on established
LTP. Additional experiments examined the ability of shorter TPS
episodes to erase LTP and found that a 30 sec treatment was effective
at 30 sec but not 15 min after induction. When the duration of TPS was
further reduced to 15 sec, a reversal was no longer obtained at any
delay. These results provide the first demonstration that the limited vulnerability of LTP to reversal by TPS, originally observed in vitro, also holds true for LTP in the awake animal and occurs along the same time frame, supporting the notion that LTP stabilization mechanisms take less than 30 min to be complete.
Key words:
depotentiation; in vivo; hippocampus; LTP
reversal; consolidation; chronic recording; retrograde amnesia; memory; TPS; depression; forgetting
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INTRODUCTION |
Behavioral studies have shown that
various manipulations can disrupt the stable encoding of memory if
applied shortly after initial learning and thereby produce retrograde
amnesia (McGaugh, 1966 ; McGaugh et al., 1993). The question naturally
arises whether long-term potentiation (LTP) passes through a
similar consolidation period during which it is susceptible to
disruption. The first evidence suggestive of a vulnerable phase for LTP
came from a study showing that transient hypoxia occurring within a few
minutes after high-frequency stimulation prevented the stable formation of LTP in hippocampal area CA1 but was ineffective at longer delays (Arai et al., 1990b). An alternative approach to address the
reversibility of LTP is to examine activity-dependent depotentiation,
defined as a lasting decrement in synaptic efficacy induced by
activation of the same set of pathways that were tetanized
previously. Most initial observations on depotentiation were done in
vitro and used stimulation protocols that differed in frequency,
duration, and time of reversal attempt across laboratories, making it
difficult for a coherent picture to emerge (Fujii et al., 1991; Wexler
and Stanton, 1993; Bashir and Collingridge, 1994; O'Dell and Kandel, 1994; Barr et al., 1995; Wagner and Alger, 1995). One study examined LTP reversal in area CA1 of freely moving rats and found that, of the
two frequencies tested, 5 Hz was significantly more effective than 1 Hz
(Stäubli and Lynch, 1990). That there might be an optimal frequency and time for reversing LTP was subsequently confirmed in
hippocampal slices; a 30 sec episode of 5 Hz stimulation named theta
pulse stimulation (TPS), delivered within <1 min after LTP induction,
completely reversed LTP, whereas 1 Hz stimulation had no impact and
stimulation at 10 Hz was no more effective than TPS (Larson et al.,
1993). That the reversal was optimally elicited by stimulation in the
theta frequency range was attributed to the fact that it imitates
endogenous hippocampal firing activity typically present during
exploration (Ranck, 1973; Bland et al., 1980). Using TPS in follow-up
experiments revealed that a 1 min episode 30 sec after LTP induction
produced a complete reversal but had increasingly less impact at longer
delays and virtually no effect at 30 min. Increasing the duration of
TPS did not produce more depotentiation, whereas decreasing it reduced
the degree of reversal (Stäubli and Chun, 1996a,b).
To assess the behavioral relevance of the above physiological findings,
it is essential to determine whether the limited window of
vulnerability to reversal observed in slices holds true for CA1 LTP in
the awake animal. None of the recent studies on depotentiation in area
CA1 has examined the time frame of reversibility or investigated whether the depression induced at a given time point is enduring and
synapse-specific (Errington et al., 1995; Doyère et al., 1996;
Doyle et al., 1997; Hölscher et al., 1997; Manahan-Vaughan, 1997). The present study focused on TPS and its ability to produce a
homosynaptic reversal of LTP at increasing delays after induction. The
goal was to establish whether the time course of reversal in the freely
moving rat corresponds to that found in slices and to determine the
minimum stimulation necessary to obtain the effect.
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MATERIALS AND METHODS |
Subjects. Twenty-six adult male Long-Evans rats, 3 months of age at the time of surgery, were used. The animals were
housed individually and kept in a 12 hr light/dark cycle with food and water available ad libitum. The animal care and use protocol
for the present study was approved by the New York University Animal Welfare Committee.
Preparation for chronic hippocampal physiology. Preparation
of animals with chronically implanted electrodes followed procedures essentially as described in a previous study (Stäubli and
Scafidi, 1997). Subjects were deeply anesthetized with pentobarbital
(65 mg/kg) and pretreated with atropine (0.1 mg/kg) to prevent
excessive salivation. A Teflon-insulated platinum-iridium recording
electrode (75 µm) was lowered under stereotaxic guidance into stratum
radiatum of hippocampal area CA1 (coordinates of 3.8 mm posterior and
2.5 mm lateral to bregma). Two Formvar-coated stainless steel monopolar stimulating electrode (125 µm) were positioned into field CA3, one in
each hemisphere (coordinates of 3.5 mm posterior and 3.0 mm lateral to
bregma), to activate independent sets of Schaffer collateral and
commissural projections converging on the population of dendrites
sampled by the ipsilateral recording electrode. An indifferent
electrode (125 µm, Formvar-coated stainless steel) with 2 mm of
insulation removed from the tip was lowered anterior to the
hippocampus, and a stainless steel bone screw over the cerebellum
served as a ground. The final depth of the electrodes was adjusted by
maximizing the amplitude of the negative-going dendritic field EPSPs
elicited by single stimulation pulses to the ipsilateral and
contralateral stimulating electrode. After these steps, the leads of
the electrodes were connected to a head stage that was permanently
affixed to the rat's skull.
LTP induction. The rats were allowed ~10 d for recovery
before being acclimated to a chronic recording cage (30 × 30 × 58 cm) and the attachment of a recording lead to their head stage. Biphasic stimulation pulses were provided by a custom built
computer-operated digital stimulator that allowed precise control of
current intensity and pulse duration. Current intensity (23-64 µA)
and pulse width (100-150 µsec) were adjusted to produce a response
that was 50-60% of the maximum amplitude of the population spike-free
response, which typically ranged between 7 and 8 mV. Recording signals
were preamplified 10× via a field effect transistor operational
amplifier built into the recording lead and fed into a second stage
amplifier set to a gain of 10, with a bandpass of 1 Hz to 5 kHz. The
evoked responses were monitored on a storage oscilloscope and fed into a personal computer running customized software with a Keithley Instruments (Cleveland, OH) Metrabyte interface board, which digitized a 30 msec sweep at 10 kHz. The initial slope and peak amplitude of each
response was measured on-line, and the average waveform of groups of
four successive responses was stored on disk for off-line analysis.
Baseline evoked EPSPs were tested alternately on the two electrodes at
15-20 sec intervals during baseline periods and after attempts to
induce LTP-reverse LTP. Baseline periods were conducted daily during
30-45 min for at least 2 d, and only those animals with  10%
variability in size of the evoked response (initial slope and
amplitude) over 2 consecutive days were used. Approximately 75% of the
animals implanted met this criterion. LTP was induced on the subsequent
day after 30 min of baseline recording. To elicit LTP, theta burst
stimulation (TBS) consisting of two sets of five theta bursts
separated by 30 sec (2 × 5 TBS), with each burst involving four
pulses at 100 Hz and paced at 200 msec, was given to the test pathway.
Current intensities and pulse widths were increased during TBS to
elicit a very small (<0.5 mV) population spike but otherwise were kept
constant throughout the entire experiment.
LTP reversal. To determine whether the reversal of LTP is
time-dependent and, if so, whether the degree of depotentiation is
contingent on the duration of the reversing stimulation, the following
protocols were tested.
(1) A 1 min train of TPS, consisting of 300 single pulses paced at the
period of the theta rhythm (200 msec), was given to the test pathway 30 sec after TBS had been used to induce LTP in a group of five rats.
Responses to both ipsilateral and contralateral pathway (test and
control response) were monitored immediately thereafter for ~2.5 hr
and again on subsequent days. If a reversal of LTP was obtained and
still present at least 3 d later, then a second episode of TBS
(2 × 5) was given to the same pathway, and the stability of the
newly induced LTP was monitored for several days. This exact protocol
was repeated in two additional groups of rats, except that the TBS-TPS
interval was increased to 15 (n = 5) and 30 (n = 6) min, respectively. In all cases, the control pathway, which did not receive TBS and TPS, was monitored throughout the experiment to determine whether the reversal obtained in the test
pathway was input-specific.
(2) The second set of experiments involved a new group of rats
(n = 5) and a TPS episode that was reduced in half to
150 pulses (30 sec episode). If a reversal of potentiation was obtained
with TPS delivered 30 sec after LTP induction and still present 3 d later, then a second TBS treatment was given to the same pathway to
reinstate LTP, followed 15 min later by attempts to reverse the
potentiation with a second TPS episode of 150 pulses.
(3) The third series of experiments involved a new group of five rats
but otherwise was identical to the set described immediately above,
except that the TPS episode was reduced to 75 pulses (i.e., 15 sec duration).
Statistics. All data are expressed as mean ± SEM
percentage baseline EPSP slope. Group means of averages for four
consecutive responses were constructed, and effects were analyzed by
conducting within-animal comparisons using the paired two-tailed
t test for average values collected over a specified 5-10
min period. Typically, the average response obtained during the last 10 min before TBS served as reference and was compared with the average
response acquired during the last 5 min of the LTP recording period
immediately preceding TPS (except for experiments involving a 30 sec
TBS-TPS interval). Similarly, the average response obtained during the last 10 min before TBS was compared with the average response collected
during the first 5 min immediately after TPS, as well as with the very
last 10 min of each recording period conducted on the same and
subsequent days.
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RESULTS |
Consistent with earlier studies (Stäubli and Lynch, 1987,
1990; Stäubli and Scafidi, 1997), TBS reliably produced LTP in all the rats, and control responses remained unaffected by any of the
high- and low-frequency stimulation treatment. Moreover, there was no
evidence that prolonged low-frequency stimulation ever induced
epileptiform activity or afterdischarges. (1) TPS of 300 pulses
administered 30 sec after LTP induction resulted in an immediate and
complete reversal of potentiation that persisted for the duration of
the 2.5 hr test session and was still present 72 hr later. As
illustrated in Figure
1A, the test response
was significantly potentiated after TBS
(T(4) = 5.95; p < 0.01) but was no longer different from baseline both immediately and 72 hr after TPS (T(4) = 0.39;
p > 0.1; and T(4) = 0.78; p > 0.1, respectively). No evidence of synaptic
suppression of the control response (n = 4) was found,
as illustrated in Figure 1B for a typical case (in
one rat, the control response was not measurable). Three days after the
reversal, TBS without subsequent TPS was administered to the same
pathway, resulting in a significant potentiation that remained for
4 d (72 hr after TBS, T(4) = 5.36; p < 0.01). In one rat, the response was lost on
day 4, and recording was therefore stopped.
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Figure 1.
Stable reversal of LTP by theta pulse stimulation
delivered 30 sec after induction of LTP in area CA1 of the freely
moving rat. A, Group data from five animals showing that
a 1 min train of TPS administered 30 sec after TBS caused a lasting
reversal of LTP. A second TBS episode administered 3 d after TPS
produced a potentiation effect that was stable for the 4 d of
recording thereafter. Each data point represents the group mean ± SEM (averages of 4 successive responses per animal and data point,
except for the 4 individual responses within the TBS-TPS interval) of
the initial slope of the dendritic field potential expressed as
percentage of the baseline. B, Individual representative
experiment on treatment days from one of the five rats shown in
A. Top, Representative population EPSPs
of control and test pathway measured at different time points during
the experiment, as indicated by the numbers in the graph
below. The solid waveforms indicate the size of the
baseline EPSPs, and the superimposed dotted waveforms
represent control and test responses recorded at the specified times.
Each waveform represents the average of four successive
responses to single-pulse stimulation at 0.05 Hz. Calibration: 3 mV, 10 msec.
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Delaying the administration of TPS by 15 min again resulted in a rapid
and complete LTP reversal, virtually identical to that observed with a
30 sec TBS-TPS interval. As illustrated in Figure 2A, the test response
in all five animals was significantly increased after TBS
(T(4) = 3.88; p < 0.01) but was reset to baseline by TPS, an effect that took place
immediately and persisted for several days
(T(4) = 0.89; p > 0.1; and T(4) = 1.5; p > 0.1, for immediate and 72 hr post-TPS recording periods,
respectively). On day 3 after TPS, a second TBS episode was
administered to the test pathway, which resulted in significant
potentiation that persisted for 4 d (2.5 hr after TBS,
T(4) = 6.13; p < 0.01; 24 hr after TBS, T(4) = 9.86;
p < 0.01; and 96 hr after TBS,
T(4) = 3.72; p < 0.05). Control responses, which were present in four of the five rats in this group, again remained unaffected (see Fig. 2B
for a typical case).
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Figure 2.
Stable reversal of LTP by theta pulse stimulation
delivered 15 min after LTP induction in area CA1 of the freely moving
rat. A, Group data from five animals showing that a 1 min train of TPS administered 15 min after TBS caused a lasting
reversal of LTP. A second TBS episode administered 3 d after TPS
produced a potentiation effect that was stable for the 4 d of
recording thereafter. Each data point represents the group mean ± SEM (averages of 4 successive responses per animal and data point) of
the initial slope of the dendritic field potential expressed as
percentage of the baseline. B, Individual representative
experiment on treatment days from one of the five rats shown in
A. Top, Representative population EPSPs
of control and test pathway measured at different time points during
the experiment, as indicated by the numbers in the graph
below. The solid waveforms indicate the size of the
baseline EPSPs, and the superimposed dotted waveforms
represent control and test responses recorded at the specified times.
Each waveform represents the average of four successive
responses to single-pulse stimulation at 0.05 Hz. Calibration: 3 mV, 10 msec.
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When TPS was delivered 30 min after LTP, a reversal of potentiation was
no longer obtained. Within-animal comparisons using the paired
t test for average values collected over the last 10 min
before TPS with the last 10 min of that recording session was not
statistically different (T(5) = 1.25;
p < 0.1), indicating that TPS was not effective at
depressing the potentiated synapses. As illustrated in Figure
3A, TBS administered to the
test pathway induced a potentiation
(T(5) = 15.9; p < 0.01) that persisted for the 4 d of recording
(T(5) = 7.82; p < 0.01). In two of the rats, TPS caused a temporary depression of the
potentiated response to levels above baseline, which recovered to the
previously potentiated level within 5 min in both animals (see Fig.
3B for an example). Control responses were present in three
of the six rats and again remained unaffected by TPS given to the test
pathway.
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Figure 3.
Failure to obtain LTP reversal when theta pulse
stimulation is administered 30 min after induction. A,
Group data from six animals illustrating that LTP was not affected by a
1 min train of TPS delivered 30 min after induction and continued to
persist for the 4 d of recording thereafter. Each data point
represents the group mean ± SEM (averages of 4 successive
responses per pathway and data point) of the initial slope of the
dendritic field potential expressed as percentage of the baseline.
B, Individual representative experiment from one of the
six rats shown in A. Top, Representative
population EPSPs in control and test pathway measured at different time
points during the experiment, as indicated by the
numbers in the graph below. The solid
waveforms indicate the size of the baseline EPSPs, and the
superimposed dotted waveforms represent control and test
responses recorded at the specified times. Each waveform
represents the average of four successive responses to single-pulse
stimulation at 0.05 Hz. Calibration: 3 mV, 10 msec.
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(2) Reducing the duration of TPS from 1 min to 30 sec (150 as opposed
to 300 pulses) resulted in a complete reversal of potentiation when
delivered 30 sec after TBS. As shown in Figure
4, the test response was significantly
potentiated by TBS (T(4) = 4.52;
p < 0.01) but decayed back to baseline after TPS. In
three of the rats, the return to baseline occurred gradually over the
course of 15-30 min, whereas in the remaining two subjects, the
reversal was complete at once. Although the average response was above baseline in the first 5 min after TPS, the difference was not significant (T(4) = 2.1;
p > 0.05). At the end of the 2.5 hr recording session,
the test response was indistinguishable from baseline (T(4) = 0.23; p > 0.1). On post-TPS day 3, a second episode of TBS was delivered to
the same pathway, causing a significant increase in the response
(T(4) = 9.24; p < 0.01). LTP was monitored for 15 min, after which a 30 sec treatment of
TPS was administered. However, unlike previously, no reversal of
potentiation was obtained (10 min before TPS vs last 10 min of
treatment day; T(4) = 0.93; p > 0.1), indicating that a 15 min TBS-TPS interval
exceeds the time frame during which LTP is susceptible to reversal by a
reduced TPS treatment. The test response remained potentiated for the 4 d of recording afterward. Four of the five rats in this group exhibited a response in the control pathway, which remained unaffected by both TPS treatments.
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Figure 4.
Reducing the duration of theta pulse stimulation
shortens the time frame during which the stimulation is effective at
reversing LTP. Group data from five animals illustrating that a 30 sec
train of TPS (150 pulses) was sufficient to cause a persistent reversal
of LTP when administered 30 sec after induction but failed to have any
impact on LTP when administered 15 min after LTP induction. Each data
point represents the group mean ± SEM (averages of 4 successive
responses per animal and data point, except for the 4 individual
responses within the 30 sec TBS-TPS interval) of the initial slope of
the dendritic field potential expressed as percentage of the
baseline.
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(3) When the duration of TPS was further reduced to 15 sec (75 pulses),
it became ineffective at reversing LTP, even when administered at the
shortest TBS-TPS interval, i.e., at 30 sec after LTP induction. As
illustrated in Figure 5, the test
response was significantly enhanced by TBS in the first 30 sec
(T(4) = 5.38; p < 0.01) and, despite the delivery of TPS, remained potentiated for the
next 48 hr (T(4) = 7.7;
p < 0.01). Control responses, which were present in
three of the five rats, remained unaffected by TPS to the test
pathway.
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Figure 5.
Fifteen seconds of theta pulse stimulation is too
short to produce a reversal of LTP. Group data from five animals
illustrating that a reduction in TPS duration to 15 sec (75 pulses)
eliminates its capacity to reverse LTP. Each data point represents the
group mean ± SEM (averages of 4 successive responses per animal
and data point, except for the 4 individual responses within the 30 sec
TBS-TPS interval) of the initial slope of the dendritic field
potential expressed as percentage of the baseline.
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Further analysis using a one-way ANOVA with repeated measures of the
normalized EPSP slope values revealed that, for the groups of rats that
exhibited TPS-induced LTP reversal, there was no significant difference
in the amount of reversal obtained during the last 10 min of recording
on treatment day (F(2,12) = 0.82; p > 0.1). Also, the same statistical comparisons were
conducted to determine whether the amount of potentiation of the EPSP
slope during the last 10 min on treatment day differed among the groups of rats that either exhibited no reversal or when no TPS was
administered to the potentiated synapses
(F(4,21) = 0.79; p > 0.1).
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DISCUSSION |
The present findings show that LTP in area CA1 of the freely
moving rat exhibits a time window of vulnerability of <30 min after
induction, after which it becomes resistant to disruption by TPS. The
same 1 min stimulation episode had no effect when administered before
LTP induction, did not cause generalized disturbances of hippocampal
activity, and equally important, did not affect heterosynaptic,
control-evoked potentials. LTP reversal always occurred rapidly and
persisted for several days. The lack of any depressive action of TPS on
pre-LTP responses, although some percentage of the synapses were
presumably already potentiated by earlier learning experiences, is
consistent with our finding that TPS-induced reversal only occurs for a
relatively brief interval after induction of LTP.
The duration of the vulnerable phase observed in the present study is
virtually identical to that established earlier in hippocampal slices
using the same TPS protocol (Stäubli and Chun, 1996a). However,
the in vivo results differ with respect to the magnitude of
the effect. In the intact hippocampus, LTP reversal was typically expressed in an all-or-none manner, i.e., the potentiation always fully
reversed to baseline value when TPS was delivered within the vulnerable
period. In slices, on the other hand, the degree of depotentiation
progressively declined as the interval between LTP induction and
reversal attempt approached 30 min.
It has been reported recently that LTP in the dentate gyrus of
anesthetized rats exhibits a vulnerable phase of <10 min during which
it can be reversed by low-frequency stimulation at 5 Hz but not 1 Hz
(Martin, 1998). Thus, the factors regulating the reversibility of LTP
in different hippocampal subfields may vary with regard to time
dependence and magnitude of effect, depending on cell type and/or state
of consciousness of the animal. Related to the above may also be the
finding that 10 stimulation bursts delivered sequentially on the
negative phase of the sensory-evoked theta rhythm in anesthetized rats
partially reverse CA1 LTP established 30 min earlier (Hölscher et
al., 1997). That naturally occurring hippocampal activity in the theta
frequency range may indeed contribute to experience-dependent erasure
of LTP is suggested in a recent report, showing that exploration of a
novel environment causes a reversal of LTP within a defined time window
of 1 hr. Exploration of the novel environment was accompanied by
increased electroencephalic activity in the theta range and was
selectively associated with the processing of new information (Xu et
al., 1998). The existence of an experience-dependent LTP reversal
effect within a defined time window raises the possibility that loss of
recent memory can result from an active process triggered by
physiological patterns associated with particular behavioral states.
Chronic unit recording studies in our and other laboratories have
established that hippocampal pyramidal cells in behaving rats fire in
single-spike mode synchronized to ongoing theta activity for periods
lasting several seconds (Bland et al., 1980; S. Wiebe and U. Stäubli, unpublished observations). The present study revealed that the minimum TPS necessary to trigger a reversal consists
of 150 pulses, a treatment only effective if applied at 30 sec but not
15 min after induction. A 15 sec TPS episode, on the other hand, was
too short to cause depotentiation at any delay. This is not to say that
15 sec of TPS would not have been sufficient to reverse LTP of lesser
magnitude, i.e., the kind of submaximal potentiation obtained when
using fewer than 10 theta bursts (Larson and Lynch, 1986). No attempts
were made to apply TPS for >60 sec, because the amount of reversal
obtained by a 3 min train in slices was found indistinguishable from
that obtained with a 1 min train (Stäubli and Chun, 1996a).
Moreover, a main objective of the present study was to determine the
minimum TPS duration necessary to reverse LTP. If electrical
stimulation-induced LTP represents the type of increase in synaptic
strength that naturally occurs to a much smaller degree at a given
synapse during learning, then it is perhaps not unreasonable to assume
that a few seconds worth of endogenous theta pulse firing activity
might be sufficient to reverse recent learning-induced increments in synaptic strength.
The observation that TPS becomes increasingly less effective as the
time since induction progresses until LTP is no longer reversible at 30 min suggests that the low-frequency stimulation triggers a mechanism
that directly antagonizes the effect of consolidation chemistries and
is effective up to the completion of LTP stabilization. An indication
as to the type of chemistries that might be involved in stabilization
comes from in vitro studies showing that peptides that block
ligand binding by integrin adhesion receptors prevent the stabilization
of LTP, without affecting its initial development or baseline
physiology (Stäubli et al., 1990; Xiao et al., 1991), and, most
importantly, cause a steady decay of LTP, even when applied after
induction (Bahr et al., 1997). Moreover, integrin antagonism was found
to produce progressively less depotentiation as the interval between
LTP induction and drug application increased, until it had no longer
any impact at 30 min (Stäubli et al., 1998). This close
similarity between the in vitro time courses for LTP
reversal by integrin antagonism versus TPS implies that integrin
activation may be a critical step in the consolidation of LTP and
suggests that the two effects may be linked. What remains to be tested
is whether intracerebral injections of antagonist into freely moving
animals affects recently induced potentiation over the same 15-30 min
time frame as TPS.
A possible route whereby TPS could deactivate integrins and thereby
disrupt the stabilization of recently induced LTP is provided by
adenosine receptors. Specifically, prolonged low-frequency pulse
stimulation at 5 Hz, but not brief high-frequency burst stimulation,
was found to preferentially cause the release of adenosine at synaptic
sites (Cunha et al., 1996). Moreover, adenosine receptors have been
implicated in suppressing integrin activation (Thiel et al., 1996).
Linked to the above is evidence that application of adenosine within a
limited time after induction reverses LTP (Arai et al., 1990a), and
blockade of adenosine A1 receptors prevents depotentiation by TPS
(Larson et al., 1993; Stäubli and Chun, 1996b). Combined, the
above collection of results support the hypothesis that TPS, via its
stimulatory action on adenosine release, suppresses the mobilization of
integrins and thereby prevents the stabilization of changes in synaptic
anatomy responsible for the persistence of LTP. It remains for future
experiments to test the strength of the above conjecture.
In a more general sense, the existence of a time-dependent LTP reversal
effect in the intact and awake hippocampus raises issues regarding its
possible role in memory. Establishment of a relationship between the
two would require comparisons of how the reversal of LTP in freely
moving rats affects recently encoded memories. However, the difficulty
with such an experiment is to establish that a sufficient number of
synapses recruited by the LTP stimulating electrode are the same as
those mediating the learning task. Perhaps more pertinent to the above
question is the observation that the post-trial consolidation period
during which newly acquired memories are susceptible to disruption by temporary inactivation of hippocampal processes (excluding lesions) is
typically on the order of 15 min to < 1 hr (Duncan, 1949; Riccio et al., 1968; Popik et al., 1994). That two very different phenomena, such as LTP and memory, exhibit vulnerable phases of very similar duration is intriguing and encourages the suggestion that the lasting
encoding of memory and the stabilization of LTP are both regulated by
the same cellular chemistries.
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FOOTNOTES |
Received March 30, 1999; revised July 16, 1999; accepted July 23, 1999.
This work was supported in part by the Whitehall Foundation (M97R05 to
U.S.).
Correspondence should be addressed to Dr. Ursula Stäubli, Cortex
Pharmaceuticals, Inc., 15231 Barranca Parkway, Irvine, CA 92618.
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ABSTRACT
INTRODUCTION
