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The Journal of Neuroscience, February 1, 1998, 18(3):887-894
Primed Facilitation of Homosynaptic Long-Term Depression and
Depotentiation in Rat Hippocampus
Lorne L.
Holland and
John J.
Wagner
Department of Pharmaceutical Sciences, College of Pharmacy, North
Dakota State University, Fargo, North Dakota 58105
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ABSTRACT |
Previous studies have demonstrated that prior synaptic activity can
influence the subsequent induction of synaptic plasticity in the brain.
Such temporal modulation of synaptic plasticity has been called
"metaplasticity." In this report, we describe the facilitatory
effects of high-frequency stimulation on the induction of homosynaptic
long-term depression (LTD) in the CA1 region of the rat hippocampus.
The LTD induced by low-frequency stimulation (1 Hz) protocols was found
to be homosynaptic and NMDA receptor-dependent. The facilitatory
effects of the high-frequency stimulation-induced priming event itself
were found to be NMDA receptor-independent and to have a duration of at
least 90 min. The effects of priming also were heterosynaptic, because
the induction of synaptic plasticity by low-frequency stimulation was
enhanced at an unprimed synaptic pathway after the priming of an
independent pathway. In addition to enhancing LTD, priming also
enhanced the reversal of long-term potentiation elicited by a 5 Hz
depotentiation protocol. Our results provide examples of how
metaplasticity may play a key role in the ongoing modulation of the
induction and stabilization of alterations in synaptic strength.
Key words:
synaptic plasticity; LTP; LTD; depotentiation; priming; metaplasticity; hippocampus
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INTRODUCTION |
Activity-dependent modulation of
synaptic plasticity is an important component in the current
understanding of the cellular mechanisms underlying learning and memory
functions of the brain (Abraham, 1996 ; Abraham and Bear, 1996). The
term metaplasticity has been suggested to encompass these phenomena,
which generally involve some previous synaptic activity that results in
a change in the capabilities of the synapse to undergo subsequent
plasticity (Bear, 1995). Such temporal plasticity of synaptic
plasticity can last for minutes to hours and is present in the absence
of any discernible effects on baseline levels of synaptic transmission. Metaplasticity may be particularly relevant in the study of long-term depression (LTD), because there have been significant discrepancies in
both past and recent literature concerning the occurrence of homosynaptic LTD induced by low-frequency stimulation (LFS; 1 Hz) in
the hippocampal formation of adult rats (see Wagner and Alger, 1996;
Heynen et al., 1996; Staubli and Scafidi, 1997). One consistent finding
in this literature is that the occurrence of previous synaptic activity
significantly enhances the likelihood of subsequently observing LTD
(Christie and Abraham, 1992; Wexler and Stanton, 1993; Wagner and
Alger, 1995). Because LFS-induced LTD can be observed under certain
conditions, it would seem that this form of LTD is deserving of
continued attention as a potentially important plasticity component in
the processing of information by neuronal networks.
In this report, we have examined the modulatory effects of a
high-frequency stimulation (HFS) priming protocol on the subsequent induction of LTD and depotentiation in the CA1 region of rat
hippocampal slices. The properties of this LTD expressed after a
priming event (i.e., primed LTD) were compared with those of the
typical LFS-induced homosynaptic LTD. In addition, the priming
phenomenon itself was characterized with respect to its duration and
its pathway specificity. A recent study has suggested that after the
induction of protein synthesis-dependent LTP (late LTP), a temporal
window exists that allows stabilization of heterosynaptic early LTP
such that it too becomes late LTP (Frey and Morris, 1997). Although
this would allow for the long-term storage of associated events, it
would also potentially result in the inappropriate storage of
extraneous information. Because our priming protocol is comparable with
those used to elicit late LTP, we tested the hypothesis that the
effects of late LTP induction at one set of synapses might also impact the efficacy of LTD or depotentiation protocols at another, independent set of synapses. Indeed, we find that priming does have heterosynaptic effects, resulting in an enhancement of both LTD and depotentiation in
the heterosynaptic pathway. We propose that the primed facilitation of
LTD and/or depotentiation after the induction of late LTP may represent
examples of "safeguard" mechanisms that act to prevent or decrease
the storage of extraneous information.
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MATERIALS AND METHODS |
Extracellular electrophysiology. Freshly prepared
transverse hippocampal slices (500 µm) were obtained from mature
(40-80-d-old) Sprague Dawley rats that had been anesthetized
(halothane) before decapitation. The CA3 region was removed surgically
immediately after slice dissection. Slices were then submerged in a
recording chamber and perfused continuously with saline saturated with
95% O2/5% CO2 at ~1 ml/min. The
recording chamber and perfusion saline were then warmed to ~29°C
for the duration of the experiment. The slices were incubated for at
least 1 hr in the chamber before an experiment was begun. The saline
contained (in mM): NaCl 120, KCl 3, MgCl2 1.5, NaH2PO4 1, CaCl2 2.5, NaHCO3 26, and glucose 10. Extracellular recording
electrodes (1-2 µm tip) were filled with 200 mM NaCl and
placed in the stratum radiatum of CA1. The field EPSP population
responses were evoked with a bipolar stimulating electrode (Kopf
Instruments, Tujunga, CA) placed on either the CA3 or the subicular
side of the recording electrode in the stratum radiatum. Stimulation
parameters consisted of single square waves of 40-100 µA of 300 µsec duration. Data were digitized at 10 kHz and analyzed with pCLAMP
6 software (Axon Instruments, Foster City, CA). The initial slope of
the population EPSP was measured by fitting a straight line to the
first millisecond of the EPSP immediately after the fiber volley
artifact.
Stimulus-response curves were performed at the beginning of each
experiment. Pulses of an intensity that gave 40-60% of the maximum
response were given at a frequency of 0.05 Hz for the remainder of the
experiment. All stimulation protocols were performed at the test pulse
intensity, and when two synaptic pathways were monitored, their
independence was evaluated as described previously (Wagner and Alger,
1995). The 1 Hz LFS protocol consisted of a 10 min period of 1 Hz
stimulation that was repeated after a 10 min interval. The 5 Hz LFS
protocol consisted of a 1 min period of 5 Hz stimulation that was
repeated after a 2.5 min interval. For clarity, the responses during
LFS are not illustrated in the figures. Priming (and/or late LTP
induction) was induced using two sets of three HFS (100 Hz/1 sec)
trains given at an interval of 20 sec, with 15 min between sets. Early
LTP was induced by using a single 100 Hz/1 sec train. This
single-tetanus protocol produced LTP (defined as a  20% increase in
field EPSP slope) lasting <3 hr in a group of control slices
(n = 4).
Quantification of synaptic plasticity. LTD was quantified
25-30 min after the completion of the LFS protocol by averaging the
EPSP slopes from 15 consecutive responses at baseline frequency and
dividing this value by the average of the 15 EPSP slopes from 5 min
before beginning LFS. Depotentiation was quantified by defining the
amount of potentiation remaining 15 min after the last HFS as 100%,
and then determining the percentage of potentiation remaining after
LFS, as was performed for LTD. Control values for depotentiation (i.e.,
rundown of LTP) were obtained using control groups of LTP experiments
that did not undergo LFS. Unless otherwise noted, the n
values reported represent slices taken from different animals for a
given experimental group (e.g., n = 6 is six slices
obtained from six different animals).
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RESULTS |
Primed LTD is similar to typical LFS-induced LTD
The field EPSP was monitored in the stratum radiatum of the CA1
region in response to stimulation of the Schaffer collaterals. An LFS
protocol consisting of two episodes of 1 Hz stimulation/600 pulses
separated by a 10 min interval was used in the attempt to elicit LTD.
As shown in Figure 1A,
1 Hz stimulation had little effect on the baseline response in slices
obtained from 40- to 80-d-old rats (92 ± 3%, n = 6 slices from four animals). In contrast, a significantly enhanced
depression was observed (77 ± 2%, n = 6) when an
HFS priming protocol preceded the LFS episodes (at * *, the tetani were
administered in the presence of DL-APV, 100 µM, to prevent LTP) (Fig. 1B).
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Figure 1.
Priming facilitates the induction of NMDA
receptor-dependent LTD. A-C, Summary
plots (n = 6 each) of normalized field EPSP measurements recorded every 20 sec from the stratum radiatum layer of
the CA1 region in hippocampal slices obtained from 6- to 11-week-old rats. The data are normalized to the 5 min period immediately preceding
the first LFS episode and the period from 25 to 30 min after the second
LFS was used to evaluate LTD magnitude. Insets are the
averages of fifteen field potential sweeps (horizontal bar is 30 msec) from representative experiments at the
indicated time points (vertical bar is 1.5 mV).
A, Two LFS episodes (600 pulses/1 Hz) resulted in a
modest, insignificant depression of the baseline response in
naïve slices. B, The same LFS was effective in
causing LTD when preceded by a priming protocol consisting of two HFS
episodes (each consisting of 100 Hz/1 sec × 3 at 20 sec
intervals, as indicated by the asterisk) performed in
the presence of DL-APV (100 µM).
C, The effects of LFS after priming were prevented in
the continued presence of DL-APV (100 µM).
D, Summary quantitation from the above experiments.
Error bars indicate the mean ± SEM from six slices. The
asterisk indicates a significant difference compared
with the other conditions (p < 0.01, ANOVA followed by Student-Newman-Keuls post hoc
tests).
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This primed LTD is dependent on the activation of NMDA receptors during
the LFS episodes, because LFS performed in the continued presence of
APV results in no significant depression from the baseline response
(98 ± 4%, n = 6 slices from five animals) (Fig. 1C). To determine the pathway specificity of primed LTD,
field EPSPs from two independent pathways were monitored during the experiments illustrated in Figure 1B (control pathway
not shown). The control pathway was significantly less affected by the
LFS of the primed pathway (89 ± 3%, n = 6;
p < 0.01, paired t test), indicating that
primed LTD has a homosynaptic component. These findings are in
agreement with other reports describing the properties of LFS-induced
LTD (Dudek and Bear, 1992; Mulkey and Malenka, 1992).
Duration of the priming effect
The results of Figure 1B establish that our
priming protocol has effects lasting for at least the 30 min allowed
for completing the APV washout. We then extended the time between the
priming protocol and LFS episodes to determine the duration of the
priming effect. As illustrated in Figure
2A, significant
facilitation of LTD still could be elicited 90 min after priming
(82 ± 3%, n = 4) when compared with temporally
matched control (i.e., LFS without priming) experiments (92 ± 1%, n = 4); however, the effects of LFS at 150 min
after priming were not significantly different from its control group
(85 ± 3% vs 89 ± 4%, respectively; n = 4 for each). Another way of considering the data is illustrated in Figure
2B, in which the degree of facilitation (primed LTD magnitude/control LTD magnitude) is plotted versus the time after the
priming protocol. These results demonstrate that the priming effect
lasts at least 1.5 and <2.5 hr.
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Figure 2.
The facilitatory effects of priming on LTD last
between 1.5 and 2.5 hr. A, Summary quantitation for
control and primed LTD experiments performed as described in Figure 1,
at the indicated priming-LFS intervals (open bars).
Error bars indicate the mean ± SEM from six, four, and four
slices at 30, 90, and 150 min, respectively, for both control and
primed groups. Asterisks Indicate a significant
difference when compared with the corresponding temporal control group
(unprimed, shaded bars) LFS group
(p < 0.01, unpaired t test).
B, Using the data from Figure 2A,
the relative increase in LTD magnitude at the indicated time points after priming is plotted (primed LTD magnitude/control LTD magnitude). For example, a doubling of LTD magnitude would be plotted as a 100%
facilitation.
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Primed facilitation of LTD is heterosynaptic
The results described in Figure 1 suggest that priming facilitates
the induction of an otherwise typical form of LTD elicited by LFS
(i.e., NMDA receptor-dependent and homosynaptic); however, the
characteristics of the priming phenomenon itself are a separate issue.
As demonstrated previously (Wagner and Alger, 1995), and shown in
Figure 1, this form of priming can be accomplished in the presence of
APV, indicating that NMDA receptor activation is not required for
priming. We also investigated the pathway specificity of priming itself
by attempting to elicit LTD in an unprimed pathway 30 min after the
priming of an independent pathway. The resulting LFS-induced depression
in an unprimed pathway (85 ± 5%, n = 8) (Fig.
3B) did not significantly
differ from any of the conditions illustrated in Figure 1. This group
result appeared to be attributable to the failure of priming to occur
in some cases, because five experiments demonstrated obvious depression (77 ± 2%), and three experiments resulted in no depression
(100 ± 3%). The underlying cause of the apparent failures to
prime in the presence of APV was not investigated extensively, although we did note that the magnitude of the transient potentiation present after the HFS protocol was nearly twofold greater in the group that
subsequently exhibited depression compared with the group that did not
(data not shown). These results suggested to us that under certain
conditions, primed facilitation of LTD indeed could be
heterosynaptic.
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Figure 3.
The effects of priming are expressed
heterosynaptically. As in Figure 1, the data are normalized to the 5 min period immediately preceding the first LFS episode, and the period
from 25 to 30 min after the second LFS was used to evaluate LTD
magnitude. A, A summary plot (n = 7)
of normalized field EPSP measurements from two independent pathways.
Priming of one pathway (asterisks) was performed as in
Figure 1, except in the absence of DL-APV, resulting in LTP
of the primed pathway (solid squares). At 30 min after priming, LFS of the unprimed pathway (1 Hz) was performed, resulting in
homosynaptic LTD (open squares). B,
Summary quantitation from the experiment above (right set of
of bars) and from a similar experiment (data not
shown), in which DL-APV was present during the priming
protocol (left set of bars,
n = 8). The open bars illustrate the
effects of LFS performed in one pathway when the second pathway had
been primed previously (i.e., heterosynaptic priming). The solid
bars illustrate the data from the primed pathways (which did
not experience LFS). Error bars indicate the mean ± SEM, and
asterisks indicate a significant depression compared with both the other pathway (p < 0.01, t test) and when compared with the data for Figure 1
A and C (p < 0.05, ANOVA followed by Student-Newman-Keuls post hoc
tests).
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Under physiologic conditions, NMDA receptors would be activated during
the priming protocol; thus, we then tested the pathway specificity of
the priming protocol in the absence of APV. In this situation, the
priming protocol has consistent, significant heterosynaptic effects on
LTD magnitude, as shown in Figure 3, A and B. LFS
of the unpotentiated pathway was given 30 min after the induction of
LTP elicited by using the HFS priming protocol in an independent
pathway. LTD in the unpotentiated, unprimed pathway (81 ± 2%,
n = 7) was significantly different from both the
control and APV groups shown in Figure 1, A and C
(p < 0.05, ANOVA followed by
Student-Newman-Keuls post hoc tests) and not significantly
different from that seen in the primed pathway (Fig. 1B). In addition, the depression retains its pathway
specificity, because the potentiated, primed pathway (Fig.
3A, solid squares) is not significantly affected
(92 ± 2%, n = 7) after LFS of the other pathway
(Fig. 3A, open squares) when compared with
control LTP experiments monitored over the same amount of time (data
not shown).
Priming results in heterosynaptic facilitation
of depotentiation
One consequence of heterosynaptic priming would be that subsequent
plasticity in independent pathways could be affected, either positively
or negatively, depending on the type of plasticity induction event. The
effects of a 5 Hz depotentiation protocol were tested on the
maintenance of single-tetanus LTP (thought to result in early LTP; see
Materials and Methods) by comparing the magnitude of the potentiation
remaining 30 min after depotentiation with the average potentiation
measured at 10-15 min after HFS (Fig.
4). Consistent with previous reports, 5 Hz stimulation is largely ineffective at reversing LTP by 15 min after
LTP induction (Fujii et al., 1991; Staubli and Chun, 1996). The
fraction of potentiation remaining 30 min after two 5 Hz episodes (1 min each, separated by 2.5 min) was not significantly different from
that seen in a control group (Fig. 4A, solid
squares) followed over the same amount of time (69 ± 6%,
n = 6, vs 79 ± 6%, n = 7, respectively). In contrast, two 5 Hz episodes resulted in significant
depotentiation relative to the time-matched control group (Fig.
4B, solid squares) when an independent
pathway (* *; otherwise not illustrated in the graph) was primed 30 min
before LTP induction (49 ± 4%, n = 5, vs 77 ± 5%, n = 5, respectively). There was no significant difference in the magnitude of potentiation induced among any of the
four single-tetanus potentiation groups (data not shown). These results
demonstrate that a significant facilitation of 5 Hz depotentiation of
one input can occur after a priming event in another, separate input
(Fig. 4D).
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Figure 4.
Heterosynaptic priming facilitates 5 Hz
depotentiation. A, A summary plot (n = 6) of the LTP produced in one pathway after a single tetanus of 100 Hz/1 sec (arrow). At 15 min after HFS, a 5 Hz
depotentiation protocol consisting of two 1 min episodes separated by
2.5 min was performed (open squares). Superimposed is
the time course of a control, single-tetanus experimental group (n = 7), which did not experience 5 Hz
depotentiation (solid squares). These control data were
renormalized to the 5 min period immediately preceding 5 Hz stimulation
to account for a small difference in the magnitude of LTP in the two
groups. B, As described in A, except the
single-tetanus HFS was preceded by multiple-tetanus priming (as
described for Fig. 3A) of an independent pathway
(asterisks, pathway not shown). A summary plot
(n = 5) of the LTP produced in one pathway after
single-tetanus HFS (arrow). At 15 min after HFS, the 5 Hz depotentiation protocol was performed (open squares). Superimposed is the time course of a control, single-tetanus group (n = 5), which also had experienced heterosynaptic
priming, but not 5 Hz depotentiation (solid squares). As
in A, these control data were renormalized to the 5 min
period immediately preceding 5 Hz stimulation to account for a small
difference in the magnitude of LTP in the two groups. C,
Schematic representations of the experiments performed in
A and B. Vertical lines
denote 100 Hz/1 sec events. The boxes represent the 5 Hz
depotentiation (DP) protocol. s1 And
s2 indicate independent synaptic pathways for the
heterosynaptic priming performed in B. D,
Summary quantitation from the experiments above. Error bars are the
mean ± SEM, and the asterisk indicates a
significant difference compared with the control LTP group
(p < 0.01, unpaired t
test).
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The effect of 5 Hz depotentiation depends on the particular form of
potentiation being reversed
Our priming protocol consists of multiple 100 Hz trains and in the
absence of APV is similar to an LTP induction protocol shown previously
to result in late LTP, a protein synthesis-dependent, long-lasting form
of LTP (Frey et al., 1993). Because of the intense nature of late LTP
induction, we hypothesized that this type of potentiation might be more
resistant to the depotentiating effects of 5 Hz stimulation than the
early LTP induction protocol described above. Consistent with this
prediction, the amount of potentiation remaining in the late
LTP-induced pathway 30 min after a 5 Hz episode (81 ± 7%,
n = 6) was not significantly different than the decline
seen in a control group followed over the same amount of time (83 ± 5%, n = 10) (Fig. 5,
A, C).
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Figure 5.
The LTP resulting from a multiple-tetanus
induction protocol is differentially sensitive to depotentiation.
A, A summary plot (n = 6) of the LTP
produced in one pathway after multiple-tetanus HFS
(asterisks, i.e., the priming protocol). At 15 min after
priming, a 5 Hz depotentiation protocol consisting of two 1 min
episodes separated by 2.5 min was performed (solid
squares). Superimposed is the time course of a control,
multiple-tetanus group of experiments (n = 10),
which did not experience 5 Hz stimulation (open
squares). These control data were renormalized to the 5 min
period immediately preceding 5 Hz stimulation to account for a small
difference in the magnitude of LTP in the two groups. B,
A summary plot (n = 4) of the LTP produced in one
pathway after multiple-tetanus HFS (asterisks).
Beginning 15 min after HFS, a 1 Hz depotentiation protocol (two
episodes of 600 pulses) was performed (solid squares). Superimposed is the time course of a control group
(n = 8), which also had experienced heterosynaptic
priming, but not 1 Hz stimulation (open squares). As in
A, these control data were renormalized to the 5 min
period immediately preceding 1 Hz stimulation to account for a small
difference in the magnitude of LTP in the two groups. C,
Summary quantitation from the experiments above. Error bars are the
mean ± SEM, and the asterisk indicates a
significant difference compared with the control pathway condition
(p < 0.01, unpaired t
test).
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The above result could imply that a pathway experiencing a strong LTP
induction protocol is in a consolidated state because of its lack of
significant depotentiation by the 5 Hz episodes. However, consistent
with our previous results using one episode of 900 pulses at 1 Hz
(Wagner and Alger, 1995), we find that two 600 pulse episodes at 1 Hz
significantly reversed the potentiation induced by multiple-tetanus
trains (Fig. 5B) when compared with a temporally matched
control group (37 + 4%, n = 4, vs 72 + 5%, n = 8, respectively). There was no significant
difference in the magnitude of potentiation induced between any of the
multiple-tetanus potentiation groups (data not shown). Thus,
consolidation of the potentiation after the multiple-tetanus induction
had not occurred, because a 1 Hz protocol still was effective in
significantly depotentiating the LTP of the primed pathway (Fig.
5C). This suggests that the reversal of late LTP is
sensitive to the particular depotentiation protocol being used.
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DISCUSSION |
Alterations in the strengths of a synaptic connections
have long been proposed to underlie the cellular mechanisms that are involved in the acts of learning and memory by the brain (Hebb, 1949).
Within this general hypothesis, the potential for bidirectional changes
in the strength of synaptic connections is crucial for preserving the
capability for change at a given synapse and for providing the maximum
flexibility and capacity of the system as a whole (Sejnowski, 1977;
Bienenstock et al., 1982). Thus, understanding the processes governing
the ability to both increase and decrease synaptic strength is central
to determining how learning and memory occur in the nervous system. In
this study, we have found that primed LTD in the CA1 region of
hippocampal slices obtained from mature rats (6-11 weeks) exhibits the
same fundamental properties as those of LFS-induced LTD in the CA1
region of hippocampal slices obtained from young (2-3 weeks) rats.
Namely, the depression is dependent on the activation of
NMDA receptors and is homosynaptic. This demonstrates that the type of
LTD induced by LFS can occur throughout the developmental life of the
animal when the conditions present during LTD induction are
appropriate. Several recent reports have found that LFS-induced LTD can
occur in the mature animal (Heynen et al., 1996; Manahan-Vaughan, 1997)
or does not occur in the mature animal (Errington et al., 1995; Staubli
and Scafidi, 1997). We would suggest that issues related to the
presence or absence of priming conditions in a particular experimental
preparation may contribute to the disparity among these studies.
In addition to bidirectional modification of synaptic strength, there
is a growing recognition of the existence of modifications of synaptic
plasticity based on previous activation of the synapse (Christie and
Abraham, 1992; Huang et al., 1992; Wexler and Stanton, 1993). Because
the effects of subsequent plasticity-inducing protocols can be altered
without an observable effect on the baseline synaptic strength, a
genuine plasticity of synaptic plasticity (i.e., metaplasticity) has
seemingly occurred. The first apparent characteristic of our form of
metaplasticity (referred to as priming in our study) is that NMDA
receptor activation was not required during HFS protocol (Wagner and
Alger, 1995). We also investigated two additional fundamental
properties of this priming protocol: the duration of the priming effect
and its pathway specificity. A significant enhancement of LTD lasted
for at least 1.5 hr, but <2.5 hr. The potential significance of this
temporal window is discussed below. Interestingly, the effect of
priming was heterosynaptic, particularly when priming was performed in
the absence of APV. Subsequent induction of LTD was facilitated in
either the primed pathway or in the unprimed, independent pathway. This
suggests that this form of priming is being manifested at synapses
throughout the postsynaptic cell. Because homosynaptic priming, as well
as some heterosynaptic priming (albeit inconsistent), occurs in the
presence of APV, we propose that the increased efficacy of
heterosynaptic priming in the absence of APV is attributable to an
enhancement of the spread of the priming effects when NMDA receptors
can be activated, rather than suggest an a priori requirement for NMDA
receptor activation in the priming of heterosynaptic pathways. In any
case, it is presumed that the absence of APV would more closely
approach the in vivo condition.
With respect to potential mechanisms of priming, several postsynaptic
possibilities have been proposed (Gold and Bear, 1994; Stanton, 1995)
and discussed recently (Bear, 1995; Abraham, 1996). These possibilities
generally involve alterations in the handling of intracellular
Ca2+ levels as a trigger for calcium-dependent
processes that then underlie metaplasticity. In addition to these
direct, postsynaptic mechanisms, it is perhaps worth noting that a form
of LTD has been described recently in stratum radiatum interneurons of
the CA1 region that is NMDA receptor-independent, heterosynaptic, and
induced by a multiple-tetanus protocol similar to our priming protocol
(McMahon and Kauer, 1997). The indirect effect of decreased inhibitory
tone after priming (i.e., disinhibition) could represent an important
contributory step leading to pyramidal cell excitation and enhanced
postsynaptic Ca2+ levels. The extensive connective
network between relatively few interneurons and many pyramidal cells in
the CA1 region (for review, see Freund and Buzsaki, 1996) would ensure
a widespread (and possibly heterosynaptic) effect of any such
disinhibition. A finding potentially related to this issue is that LTD
evoked by LFS in vivo has been found to be dependent on the
specific synaptic input being activated such that LFS of the
ipsilateral Schaffer inputs, but not LFS of contralateral commissural
inputs, results in LTD (Heynen et al., 1996). Because these two types
of synaptic stimulation are known to activate different inhibitory
circuits in the CA1 region (Andersen et al., 1964; Alger and Nicoll,
1979), a role for GABAergic systems in modulating LTD induction is
implied.
Multiple-tetanus HFS protocols, such as those used in our priming
studies, have been shown to elicit a protein synthesis-dependent form
of LTP, or late LTP (Frey et al., 1988; Otani et al., 1989; Huang and
Kandel, 1994). It has been suggested recently that late LTP induction
in a given pathway initiates a stabilization process that can spread
throughout the postsynaptic neuron and stabilize the potentiation of
less potent LTP induction protocols at other synaptic inputs. For a
period of at least 40 min after the completion of tetanization, a
weaker tetanus given at an independent pathway can "commandeer"
stabilization factors produced previously, such that it too becomes
late LTP (Frey and Morris, 1997). This heterosynaptic stabilization
could be inappropriate in certain cases and raises the question as to
how the neuron might regulate such occurrences. Because the same HFS
conditions causing late LTP in the studies cited above also facilitate
LTD induction in our preparation, we examined the role priming may have
as a safeguard mechanism by acting to limit the inappropriate
stabilization of LTP. Our results demonstrate that late LTP induction
in one pathway produces an increased effectiveness of both the baseline
depression caused by 1 Hz stimulation as well as the depotentiating
effects of 5 Hz stimulation in another, independent pathway (i.e.,
heterosynaptic priming of LTD and depotentiation). These findings
represent at least two possible ways by which inappropriate
stabilization of weak potentiation could be avoided. First, the
facilitation of LFS-induced LTD (Fig. 3) could have an inhibitory
effect on the single-tetanus induction of LTP via the 100 Hz/1 sec
protocol. Such an effect possibly is related to reports that previous
synaptic activation via 1 Hz stimulation suppresses LTP induction
(Fujii et al., 1991, 1996). An enhancement of this suppressive effect would tend to prevent the initiation of potentiation in other pathways
by weak induction protocols. Second, the facilitation of 5 Hz-induced
depotentiation (Fig. 4) could provide a means by which weak
potentiation could be reversed before it was stabilized. Increasing the
susceptibility of weak potentiation to theta rhythm-induced depotentiation would tend to erase inappropriate potentiation of other
pathways. Priming also may increase the time during which the weak
potentiation is susceptible to reversal by theta-like patterns of
stimulation (a similar effect has been reported to result during
application of a drug that facilitates glutamate receptor activity)
(Staubli and Chun, 1996). An important feature of these potential
safeguards is that they are not likely to affect true late LTP
induction and expression in the second pathway, because strong LTP
induction usually is not blocked by previous 1 Hz stimulation (Wagner
and Alger, 1995), and our results in Figure 5 show that the maintenance
of late LTP is not affected significantly by 5 Hz depotentiation. These
differential effects then allow for the preservation of the original
late LTP and the induction and maintenance of late LTP in independent
pathways while enhancing LTD and depotentiation in weakly potentiated
pathways.
In summary, our results indicate that priming resulting from multiple
HFS trains can have several implications for future occurrences of
synaptic plasticity. When considering the potential significance of a
given metaplasticity episode, it is important to appreciate that the
resulting modulatory effects will be different depending on the type of
subsequently evoked plasticity event. For example, a priming episode
can potentially inhibit an attempt to potentiate the synapse (Huang et
al., 1992) but also can facilitate depression of the synapse after
similar priming stimuli (Wexler and Stanton, 1993). In both of these
instances, a general inhibitory environment is promoted, via either
suppressed potentiation or enhanced depression. We have found that our
more intense priming protocol can facilitate the effectiveness of
depotentiation by 5 Hz stimulation in a heterosynaptic pathway, whereas
Frey and Morris (1997) have found that such an intense stimulation
pattern can promote the stabilization of weak potentiation in a
heterosynaptic pathway. Thus, both negative and positive influences on
LTP stabilization can be present after the same priming event. In this
report, we have shown that the facilitation of LTD induction in the
primed pathway and the facilitation of LTD and depotentiation in the unprimed pathway can all occur after HFS priming, in addition to the
immediate homosynaptic LTP produced. This multiplicity provides a stiff
challenge for future attempts to unravel the significance of these
interactions.
| |
FOOTNOTES |
Received Sept. 11, 1997; revised Nov. 13, 1997; accepted Nov. 17, 1997.
This work was supported by National Institute on Drug Abuse Grant
DA09603 to J.W. We thank Dr. Brad Alger and colleagues for helpful
comments on an earlier version of this manuscript.
Correspondence should be addressed to Dr. John J. Wagner, College of
Pharmacy, North Dakota State University, 123 Sudro Hall, Fargo, ND
58105.
| |
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Abstract
Introduction
