W. M. Keck Center for the Neurobiology of Learning and Memory; and the Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 77030
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ABSTRACT |
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Steele, Philip M. and
Michael D. Mauk.
Inhibitory control of LTP and LTD: stability of synapse strength.
Although much is known about the induction of synaptic
plasticity, the persistence of memories suggests the importance of
understanding factors that maintain synaptic strength and prevent
unwanted synaptic changes. Here we present evidence that recurrent
inhibitory connections in the CA1 region of hippocampus may contribute
to this task by modulating the relative ability to induce long-term
potentiation and depression (LTP and LTD). Bath application of the
-aminobutyric acid (GABA) type A agonist muscimol to hippocampal
slices increased the range of frequencies that produce LTD, whereas in
the presence of the GABA type A antagonist picrotoxin LTD was induced
only at very low stimulation frequencies (0.25-0.5 Hz). Because one source of GABAergic input to CA1 pyramidal cells is via recurrent inhibition, we tested the prediction that elevated postsynaptic spike
activity would increase feedback GABA inhibition and favor the
induction of LTD. By using an induction stimulation of 8 Hz, which
alone produced no net change in synaptic strength, we found that
stimulation presented during antidromic activation of pyramidal cell
spikes induced LTD. This effect was blocked by picrotoxin. The
influence of recurrent inhibition on LTP and LTD displays properties
that may decrease the potential for self-reinforcing, runaway changes
in synapse strength. A mechanism of this sort may help maintain
patterns of synaptic strengths despite the ongoing opportunities for
plasticity produced by synapse activation.
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INTRODUCTION |
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Activity-dependent mechanisms of
synaptic plasticity are generally viewed as a plausible neural basis
for learning and memory (Hebb 1949; Kandel and
Schwartz 1982
). In this context, learning relates to the
mechanisms for inducing plasticity, and the persistence of memory
relates to the stable and long-lasting expression of plasticity. The
phenomena of long-term potentiation (LTP) and depression (LTD), as
commonly studied in the CA1 region of hippocampus, are important in
part because of the potential relationship between their long-term
expression and the persistence of memories (Bear and Malenka
1994
; Bliss and Collingridge 1993
;
Eichenbaum 1996
).
However, forms of plasticity that display cellular and molecular
mechanisms for the long-term expression of synaptic changes, such as
LTP and LTD, do not necessarily confer synapses with the ability to
store long-term memories. Clearly, the ability of synapses to undergo
activity-dependent plasticity may allow experience to produce patterns
of synaptic strengths that permit networks to store memories. Yet
learning involves interactions between mechanisms/rules of plasticity
and the activity of the networks in which the modifiable synapses
reside. In the artificial circumstances of an in vitro brain slice,
most synapses are relatively quiescent unless stimulated by the
experimenter. Thus the long-term expression of synaptic plasticity in a
slice may require only a molecular mechanism that persists. In
contrast, modifiable synapses in the intact brain are probably active
quite often, providing frequent opportunities to change the patterns of
synaptic weights that might encode a memory. Observations that
hippocampal LTP and LTD are mutually reversing (Dudek and Bear
1993; Mulkey and Malenka 1992
) reveal that these
patterns can be changed and memories can be erased, despite the
underlying ability for LTP and LTD expression to be long lasting. For
example, potentiation at a set of synapses might encode a memory, but
the induction of LTD at some or all of these synapses could degrade or
completely erase this memory. Thus any systematic tendency for
strengths to drift would mean that the persistence of memory cannot be
explained entirely by in vitro observations that LTP and LTD expression
can be long lasting.
Understanding the processes that prevent unwanted synaptic changes and
contribute to the stability of synaptic strengths is highlighted
further by the apparent potential for self-reinforcing, runaway
induction of LTP and LTD. Because of the way these forms of plasticity
depend on the postsynaptic membrane potential (Artola et al.
1990; Larson and Lynch 1989
; Malinow and
Miller 1986
), changes in one set of synapses may increase the
likelihood for further changes in the same direction (see
Barrionuevo and Brown 1988
). For example, the induction
of LTP at one set of synapses could lead to stronger postsynaptic
depolarization and therefore increase the likelihood of subsequent
induction of LTP at all synapses onto the same postsynaptic cell. In
this case there would be a complete loss of the patterns of synaptic
weights onto the cell. Furthermore, because LTP and LTD are activity
dependent, the ongoing activity displayed throughout the nervous system
provides abundant opportunities for unwanted plasticity. Thus with
bidirectional forms of plasticity (such as LTD and LTP) that are
activity dependent and mutually reversing it seems important to
understand both the mechanisms that lead to the induction of plasticity
as well as the mechanisms that prevent the induction of unwanted
plasticity and the potential loss of memories.
Negative feedback, in which action potential activity of the
postsynaptic cell regulates excitability or the induction of synaptic
plasticity, represents one general class of mechanism that could
prevent runaway changes in activity or runaway induction of synaptic
plasticity (see Bienenstock et al. 1982). Previous studies demonstrated the existence of processes within neurons that
couple changes in synaptic strength and ion channel densities with
recent postsynaptic activity (Turrigiano et al. 1994
).
Moreover, computational studies suggest that negative feedback can
maintain the activity of neurons within a useful dynamic range
(LeMasson et al. 1993
; Tsodyks et al.
1997
). When applied to the induction of LTP and LTD, negative
feedback could prevent runaway changes by making it easier to induce
LTD (relative to LTP) when postsynaptic activity is high and by making
it relatively easier to induce LTP when postsynaptic activity is low.
Here we pursued the general hypothesis that
-aminobutyric acid
(GABA)-mediated recurrent inhibition may provide this sort of
stabilizing negative feedback in the hippocampus (Fig.
1). We tested the specific hypothesis that spike activity of the postsynaptic pyramidal cell recruits GABA-mediated recurrent inhibition and influences the induction of
plasticity by making it relatively easier to induce LTD when pyramidal
cell spike activity is high and relatively easier to induce LTP when it
is low.
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METHODS |
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Slice preparation
Methods for preparing hippocampal slices were as previously
described (Huber et al. 1995). Briefly, Harlan
Sprague-Dawley rats (5-9 wk old) were deeply anesthetized with sodium
pentobarbital (50 mg/kg) and were decapitated. The brain was rapidly
removed and immersed in ice-cold artificial cerebrospinal fluid (ACSF) saturated with 95% O2-5% CO2 and containing
the following (in mM): 124 NaCl, 3 KCl, 1.3 NaH2PO4, 10 MgCl2, 0 CaCl2, 26 NaHCO3, 10 dextrose, and 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (pH 7.35). One hippocampus was dissected free, and transverse slices (400-µM thick) were prepared with a McIlwain tissue chopper. Immediately afterward, CaCl2 (2 mM) was added to the ACSF,
which was then warmed to 31°C over 20 min. Slices were then incubated for an additional 30 min in the standard ACSF (31°C), containing the
same stock solution as described previously, except MgCl2 (1.5) and CaCl2 (2.5). Slices prepared from the same
hippocampus were pseudorandomly assigned to experimental or control
experiments. Immediately before electrophysiological recordings, the
CA1 region of all slices was surgically isolated from CA3.
Preparation of compounds
The following compounds used in this study were purchased from Sigma and prepared as follows. A muscimol stock solution (100 µM) was made fresh every other day, kept at 4°C, protected from light, and diluted in standard ACSF to 3 nM immediately before use. Picrotoxin (50 µM) was prepared daily in standard ACSF with no added CaCl2 and MgCl2 (room temperature). After the picrotoxin completely dissolved, the solution was oxygenated, and CaCl2 (2.5) and MgCl2 (1.5) were added. D,L-2-amino-5 phosphonovalerate (APV) was prepared as a stock solution (50 mM) and diluted in standard ACSF to 50 µM immediately before use.
Recordings
All experiments were performed in a standard submersion chamber
perfused with ACSF at a rate of 1.5 to 2 ml/min (31°C). Extracellular field potentials were recorded from the stratum radiatum in area CA1 of
hippocampal slices with pipette electrodes (1 to 3 M) filled with
ACSF with no MgCl2 or CaCl2 added.
Intracellular recordings were obtained from the pyramidal cell layer
with electrodes filled with 3 M potassium acetate (60-80 M
).
Schaffer collateral and commissural axons in stratum radiatum were
stimulated with tungsten monopolar (20-50 µm) electrodes (Frederick
Haer, Brunswick, ME) for 30-60 min to obtain a stable baseline.
Similar electrodes with larger exposed tips (1 mm) were placed against
the alveus to stimulate pyramidal cell axons in antidromic studies. For
each field potential experiment the stimulation intensity was set to produce synaptic responses that were ~50% of maximum, as measured by
initial slope of the excitatory postsynaptic potential (EPSP). These
responses were between 0.37 and 0.43 mV/ms with an amplitude of between
0.6 and 0.8 mV. The EPSPs recorded during intracellular experiments
were set to 10-15% below threshold for an action potential. All
experiments in which the input resistance of the pyramidal cell changed
by >20% were excluded (3 were excluded). The baseline measurements
were collected with single shocks every 15 or 30 s. Responses were
digitized at 20 kHz and stored on computer for subsequent analyses.
The induction stimulation consisted of 600 pulses delivered at frequencies ranging from 0.25 to 50 Hz. The antidromic stimulation consisted of four pulses at 100 Hz given every 500 ms for the duration of the 8-Hz induction stimulation. In most analyses, changes in EPSP slope are expressed as the average EPSP slope over the last 5 min of the experiment (40-45 min postinduction) normalized to the last 5 min of baseline. Values reported in the text and figures are mean ± SE. Two-tailed distributions with a critical P-value of 0.05 were used for all statistics.
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RESULTS |
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To test these hypotheses we began by examining the effects of a GABA type A receptor antagonist (picrotoxin) and agonist (muscimol) on the induction of LTD at the normally employed stimulation frequencies (600 pulses at 1 and 3 Hz; Fig. 2). Whereas either 1- or 3-Hz stimulation reliably induced LTD in control slices, the same stimulation protocol in the presence of picrotoxin produced only a transient decrease in EPSP slope that returned to baseline level within ~15 min (Fig. 2A). After washing out picrotoxin, the same stimulation reliably induced LTD. Application of picrotoxin after the induction of LTD had no noticeable effects (Fig. 2B), indicating that picrotoxin does not block the expression of LTD. In contrast, application of muscimol enhanced the induction of LTD compared with controls (Fig. 2C).
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We then determined whether picrotoxin blocked LTD induction completely
or simply changed the stimulation conditions required for inducing LTD
relative to LTP. We first tested the ability of stimulation frequencies
ranging from 0.25 to 50 Hz (600 pulses) to induce LTP and LTD. All
experiments were performed as shown in Fig. 2A. Control
experiments generally replicated previous findings (Dudek and
Bear 1992, 1993
; Mulkey and Malenka 1992
) by
inducing LTD at stimulation frequencies of 0.25 to 5 Hz and inducing
LTP at higher frequencies (10 and 50 Hz; Fig.
3A). Bath application of
picrotoxin had no measurable effect at 0.25 and 0.5 Hz, prevented the
induction of LTD at 1 and 3 Hz, and enhanced the ability to induce LTP
at 5 and 10 Hz (Fig. 3A). In contrast, bath application of
muscimol enhanced the ability of stimulation to induce LTD relative to
LTP (as seen at 10 Hz) and also significantly increased the magnitude
of LTD induced by stimulation at 0.5 to 3 Hz (Fig. 3B).
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The differences between each drug and control slices over the range of
stimulation frequencies tested suggest two key properties regarding the
role of GABA-mediated inhibition on the induction of LTP and LTD (Fig.
3C). First, as indicated by the relatively uniform effects
of muscimol across all but the highest frequencies, inhibition of
pyramidal cells makes it easier to induce LTD relative to LTP. Second,
as suggested by the effects of picrotoxin, endogenous GABA released at
stimulation frequencies of 1 Hz increases the ability to induce LTD
relative to LTP. These data indicate that, at stimulation frequencies
above a certain threshold (1 Hz in these experiments), endogenous
release of GABA during repetitive stimulation contributes to the final
outcome of LTD, LTP, or no change in synaptic strengths. Although there
is likely to be tonic release of GABA in slices, the discrete
divergence of the picrotoxin-treated slices from control slices at 1 Hz
suggests that the effects are due to inhibition of stimulation-induced
GABA release.
It seemed important to address the possibility that picrotoxin may
block the induction of N-methyl-D-aspartate
(NMDA)-dependent LTD and that the synaptic depression seen at 0.25 and
0.5 Hz is mediated by mechanisms that differ from those that mediate
the induction of LTD at 1 and 3 Hz. To address this we tested whether the LTD seen at 0.25 Hz (in picrotoxin) displays two key properties of
LTD, pathway specificity and dependence on NMDA receptors (Dudek and Bear 1993). As shown in Fig.
4, two pathway experiments indicate that
the synaptic depression seen at 0.25 Hz is pathway specific because no
change was seen in the responses elicited by a separate stimulation
pathway. Moreover, application of the NMDA receptor antagonist APV
blocked the induction of LTD at 0.25 Hz in picrotoxin. Thus it appears
that bath application of picrotoxin does not block LTD per se nor does
it enhance a novel form of LTD seen only at low stimulation
frequencies. Instead, bath application of picrotoxin and muscimol
appears to systematically change the conditions required for the
induction of the same NMDA-dependent, input-specific LTD commonly
studied with 1- or 3-Hz stimulation.
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In the CA1 region of hippocampus, recurrent inhibition represents one
of the possible sources of GABAergic input that could be engaged during
repetitive stimulation of Schaffer collateral afferents (Fig. 1).
Because recurrent inhibition increases as pyramidal cell activity
increases (Maccaferri and McBain 1995), the effects of
picrotoxin and of muscimol may reveal a role of negative feedback in
controlling the induction of plasticity. Our results are consistent
with the hypothesis that repetitive afferent stimulation above a
threshold level engages recurrent inhibition, aiding in the induction
of LTD. At midrange stimulation frequencies (~8-10 Hz in our
experiments) the effects of excitation and recurrent inhibition may
combine to produce no net change in synapse strength. Higher
stimulation frequencies may overwhelm this balance and lead to the
induction of LTP. In this context, enhancing inhibition (as with
muscimol) should favor the induction of LTD over LTP, whereas blocking
inhibition (as with picrotoxin) should make the induction of LTD more
difficult, as we have shown, and make the induction of LTP relatively
easier, as is often observed.
These ideas predict that the induction of LTD would be favored over LTP
when recurrent inhibition is enhanced through an artificial increase of
pyramidal cell spike activity. To test this prediction we employed a
frequency of induction stimulation (600 pulses at 8 Hz) that produced
no net change in EPSP slope in control experiments (Fig. 3). To
increase postsynaptic activity we used antidromic stimulation to elicit
action potentials in pyramidal cells and intracellular recordings to
confirm that the antidromic stimulation recruited recurrent inhibition
(Fig. 5E).
The antidromic stimulation (4 100-Hz pulses delivered
twice per second) was similar to the firing characteristics of the
inhibitory basket cells (Sik et al. 1995). Whereas 8-Hz
stimulation alone did not produce a significant change in EPSP slope
(Fig. 5A), pairing 8-Hz stimulation with antidromic
activation of spikes in the pyramidal cells reliably induced LTD (Fig.
5B). This effect was blocked by bath application of
picrotoxin, where the combination of 8-Hz stimulation and antidromic stimulation produced, if anything, an increase in the EPSP slope (Fig.
5C). Each experiment included a second pathway to control for nonspecific effect of antidromic stimulation. The means for all
three groups are shown in Fig. 5D.
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The intracellular recordings collected during the induction stimulation illustrate the interactions among the 8-Hz stimulation, the antidromic stimulation, and the bath application of picrotoxin (Fig. 5, A-C, top portions). During 8-Hz stimulation alone (which produced no significant change in EPSP slope), there was only a slight change in the underlying membrane potential (Fig. 5A). In contrast, adding antidromic stimulation (which induced LTD) produced a pronounced hyperpolarization during the 8-Hz induction stimulation (Fig. 5B). Application of picrotoxin during this combined antidromic/8-Hz stimulation (which induced LTP) produced a small depolarization. These observations are consistent with the simple notion that recurrent inhibition affects the relative ability to induce LTD and LTP by influencing the membrane potential and the degree to which repetitive stimulation can activate NMDA receptor-gated channels.
To examine this notion further, we tested the ability of the 8-Hz stimulation/antidromic stimulation combination to induce LTD in the presence of APV (Fig. 6). Bath application of APV blocked the induction of LTD, whereas after washout of APV the same combined stimulation reliably induced LTD (n = 4). These experiments also employed a second input pathway. Responses to this pathway did not change, showing that this LTD is also input specific. These observations further support the idea that increased inhibition facilitates the induction of LTD by controlling the activation of NMDA receptors.
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DISCUSSION |
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The main result we report is that the relative ability to induce LTP versus LTD is influenced by the degree of activation of recurrent inhibitory inputs. Application of the GABA type A receptor agonist muscimol or increasing endogenous recurrent GABAergic input both favor the induction of LTD relative to LTP. Thus when GABAergic activity is high LTD can be induced with stimulation protocols that normally either induce LTP or produce no change in EPSP slope. In contrast, picrotoxin increases the range of stimulation frequencies that induce LTP such that LTD induction is blocked at the stimulation frequencies employed in most LTD studies (1-3 Hz) and can be induced only at very low stimulation frequencies (0.25 and 0.5 Hz). The LTD induced at these low frequencies is pathway specific and sensitive to the NMDA antagonist (APV), suggesting that it is not a novel form of LTD. These data have a number of implications concerning both the induction of LTP and LTD in vitro and concerning the properties that LTD and LTP may display in hippocampal circuits.
Our results indicate that the induction of LTD or LTP in vitro can
involve interactions between direct excitatory input to the pyramidal
cells and recurrent inhibition that is activated by spike activity in
the pyramidal cells. Feed-forward inhibition is also likely to be
activated by each orthodromic pulse. However, because its presence is a
constant, it seems unlikely that feed-forward inhibition can explain
the ability of antidromic activation to induce LTD with 8-Hz
stimulation. Both the abolition of this effect by picrotoxin and the
picrotoxin-sensitive hyperpolarization after antidromic stimulation
suggest that recurrent inhibition may play an important role in
controlling the direction of change in synaptic strength. Because both
LTP and the LTD observed with 8-Hz/antidromic pairing are NMDA
dependent, we suggest that under normal conditions the amount of
feedback inhibition recruited by 8-Hz stimulation leads to calcium
influx that falls between the levels required to induce LTD and LTP
(Cummings et al. 1996). When inhibitory feedback is
increases, as we have done with antidromic stimulation, the decreased
amount of calcium influx favors the induction of LTD.
Our results imply that activating inhibitory synaptic transmission is required for the induction of LTD at the stimulation frequencies employed in most studies (1-3 Hz). Because picrotoxin had no effect at stimulation intensities of 0.5 and 0.25 Hz (Fig. 2A), we suggest that in our experiments the feedback inhibition is engaged at stimulation frequencies of 1 Hz and above. However, it seems likely that this threshold may vary, depending on circumstances such as the size and position of the stimulation electrodes as well as the stimulation intensities used.
Variation in the activation of inhibitory synaptic transmission may
therefore account for the variable ability to induce LTD in different
laboratories and perhaps with different aged animals (Abraham et
al. 1996; Bashir and Collingridge 1994
;
Dudek and Bear 1992
, 1993
; Thiels et al.
1994
; Yang et al. 1994
). For example, certain
studies reported that it is difficult to induce LTD in brain slices
from older animals (O'Dell and Kandel 1994
;
Wagner and Alger 1995
). One explanation for this may be
that LTD is saturated at these synapses, either because of the
animal's experiences or because of events that occur during
preparation of the slices (Bolshakov and Siegelbaum
1995
). Our data also suggest that the induction of LTD might
require different frequencies of stimulation in older animals as the
balance between excitation and inhibition changes with age
(Muller et al. 1989
; Swann et al. 1989
).
Similarly, Thiels et al. (1994)
have shown clearly that the induction
of LTD in vivo requires recurrent inhibition. Stimulation protocols such as the ones that induce LTD in vitro had no effect, as were patterns of stimulation that paired synaptic inputs with recurrent inhibition-induced robust LTD. The induction of this LTD in vivo was
blocked by bicuculline. Here again the role for recurrent inhibition
may explain the inability to induce LTD in some in vivo preparations
(e.g., Doyley et al. 1997
).
Several previous studies addressed the potential role of GABAergic
inhibition in the induction of LTD and LTP. Gustafsson and
Wigström (1990) demonstrated that the induction of LTP is enhanced when inhibitory synaptic transmission is blocked. Conversely, Yang et al. (1994)
demonstrated that the induction of LTD is
facilitated in young rats by pairing synaptic activation with GABA. Our
results and the hypothesis regarding the role of feedback inhibition
are consistent with their findings. Wagner and Alger (1995)
also
reported and extensive analysis of the influence of both
GABAA and GABAB receptors on the induction of
LTD. These authors showed that, in apparent contrast to our findings,
the GABAA antagonist bicuculline did not affect LTD in
slices taken from young animals (16-22d) and enhanced the induction of
LTD in slices from mature animals. A GABAB antagonist
significantly decreased LTD in slices from young animals but had no
effect on depotentiation (inducing LTD after the induction of LTP).
These results suggest that the effects of GABAergic transmission may be
different before and after the induction of LTP, consistent with
feedback control of LTP and LTD. These results also suggest, like our
results, that the contributions of GABAergic inhibition
and thus the
effects of GABA antagonists
vary depending on a number of factors.
Thus both previous and present data indicate 1) the
importance of testing the effects of GABA antagonists over a range of
stimulation frequencies and thus 2) that caution is required
in interpreting the implications of a pharmacological manipulation when
tested at only one stimulation frequency.
Feedback inhibition may serve the useful role of preventing runaway
induction of LTP or LTD. As mentioned previously, the induction of LTD
and LTP requires relatively strong and weak pyramidal cell
depolarization respectively, and each is potentially prone to positive
feedback. Our results suggest that inhibitory control over the
induction of LTD and LTP via recurrent pathways may help break this
positive feedback. Such a mechanism appears potentially important for
several reasons. First, a neuron whose inputs are all as strong or as
weak as possible would have a diminished capacity for processing
information. Its activity would depend mostly on the number of its
inputs that are active and would depend much less on the pattern of the
inputs. Second, with a typical number of active inputs, there would be
an increased likelihood that the spike rate of the cell would remain
almost exclusively at its maximum or minimum level. The ability of such
a uniformly active cell to pass along information to its follower cells
would be greatly diminished. Third, an inherent tendency for all
synaptic strengths to drift to their maximum or all to their minimum
values would preclude the ability of training-induced patterns of
synaptic strengths to encode memories (Sutton and Barto
1981).
The role for recurrent inhibition that our data suggest is similar to
the hypothetical rule for bidirectional synaptic plasticity proposed by
Bienestock et al. (BCM) (1982). In the BCM rule, the threshold activity
separating the induction of potentiation and depression is a function
of average recent activity of the postsynaptic cell. With increasing
activity the threshold increases such that it is easier to induce
depression, much like our observation that increased postsynaptic
activity increases the range of stimulation frequencies that produce
LTD by recruiting recurrent inhibition. Our hypothesis differs from the
BCM rule in that it is implemented with a small network involving
feedback inhibition rather than by mechanisms within the cell. It also
differs in terms of the time period over which recent activity can
influence the threshold.
Despite these differences, our hypothesis shares in common with the BCM
rule the property that the threshold between increases (LTP) and
decreases (LTD) in synaptic strengths varies as a function of recent
postsynaptic activity. Given the conceptual appeal of the BCM rule, the
existence of mechanisms that are similar or share certain important
properties (such as the one we propose) should not come as a surprise.
The important functional properties of a BCM-like rule may have led to
the evolution of many variants and forms of implementation. For
example, recent studies suggest a BCM-like negative feedback regulation
of LTD and LTP that arises from the properties of
calcium/calmodulin-dependent protein kinase II, an enzyme whose
activity is known to be involved in the induction of LTP
(Mayford et al. 1995).
Finally, our results suggest the importance of understanding not only the conditions under which synapses change in strength but also the mechanisms that are responsible for preventing unwanted changes. We suggest our results may illustrate one possible mechanism, namely, modulation of the induction of LTD and LTP via recurrent inhibition, that could help accomplish this apparently important task.
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ACKNOWLEDGMENTS |
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We thank N. Waxham, P. Kelly, K. Garcia, J. Medina, G. Kenyon, K. Huber, and A. Hudmon for comments.
This work was supported by National Institute of Mental Health Grant 46904 and by a Scholars Award from the McKnight Foundation.
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FOOTNOTES |
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Address for reprint requests: M. D. Mauk, Dept. of Neurobiology and Anatomy, University of Texas Medical School, 6431 Fannin, Houston, TX 77030.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 20 January 1998; accepted in final form 8 October 1998.
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REFERENCES |
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