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The Journal of Neuroscience, March 1, 1998, 18(5):1662-1670
Bidirectional Synaptic Plasticity in the Rat Basolateral
Amygdala: Characterization of an Activity-Dependent Switch Sensitive to
the Presynaptic Metabotropic Glutamate Receptor Antagonist
2S- -Ethylglutamic Acid
He
Li1,
Susan R. B.
Weiss2,
De-Maw
Chuang2,
Robert M.
Post2, and
Michael A.
Rogawski1
1 Epilepsy Research Branch, National Institute of
Neurological Disorders and Stroke, and 2 Biological
Psychiatry Branch, National Institute of Mental Health, National
Institutes of Health, Bethesda, Maryland 20892
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ABSTRACT |
This study examines forms of activity-dependent synaptic plasticity
in the basolateral amygdala in vitro and demonstrates that a brief high frequency stimulus (HFS) train can induce a switch in
the direction of the enduring change in synaptic strength induced by
subsequent low-frequency stimulation (LFS). LFS (1 Hz, 15 min) of the
external capsule (EC) induced a persistent 1.7-fold enhancement in the
amplitude of synaptic potentials recorded intracellularly in
basolateral amygdala neurons. The enhancement occurred gradually during
the stimulation and was maintained for >30 min after termination of
the stimulus train. LFS-induced enduring synaptic facilitation was not
affected by the NMDA receptor antagonist D( )-2-amino-5-phosphonopentanoate (APV; 100 µM). Brief high-frequency EC stimulation (HFS; 100 Hz, 1 sec) induced APV-sensitive short-term potentiation (2.5-fold) that
generally decayed within 10 min. When LFS was applied after recovery
from the short-term potentiating effect of HFS (HFS/LFS), there was an
initial transient (<10 min) enhancement of the synaptic response
followed by persistent synaptic depression (synaptic potential
amplitude reduced by 22% at 30 min). This represents the first
demonstration of stimulus-dependent long-lasting synaptic depression in
the amygdala. Application of the presynaptic (group II) metabotropic
glutamate receptor antagonist 2S- -ethylglutamic acid (EGLU; 50 µM) prevented the HFS-dependent switch from synaptic
facilitation to depression. Thus, LFS in the in vitro
amygdala slice can induce either enduring synaptic potentiation or
depression, depending on whether a priming HFS train has been applied.
This experience-dependent switch, a novel form of metaplasticity, is
not dependent on NMDA receptors but may require group II metabotropic
glutamate receptors. In the amygdala, experiential modification of
activity-dependent long-term synaptic plasticity adds flexibility to
the ways in which synaptic strength can be modified and could play a
role in diverse amygdala-dependent processes, including the formation, storage, and extinction of emotional memory and the regulation of
epileptogenesis.
Key words:
basolateral amygdala; synaptic plasticity; long-term
potentiation; long-term depression; NMDA receptor; metabotropic
glutamate receptor; 2S--ethylglutamic acid
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INTRODUCTION |
The strength of synaptic
transmission can be persistently up- or downregulated by
activity-dependent processes at excitatory synapses in the mammalian
brain. The direction and duration of the induced changes in synaptic
efficacy depend on the degree and pattern of synaptic activation. In
general, "strong" synaptic activation by brief high-frequency
tetanic stimulation (HFS) induces long-term potentiation (LTP), and
"weaker" synaptic activation elicited by prolonged low-frequency
stimulation (LFS) may induce long-term depression (LTD) (Artola et al.,
1990 ; Bear and Abraham, 1996). These bidirectional activity-dependent
modifications of synaptic strength in the hippocampal CA1 region
(Mulkey and Malenka, 1992; Dudek and Bear, 1993; Heynen et al., 1996)
and some other brain structures (Artola and Singer, 1993; Bear, 1996)
are often dependent on NMDA receptor activation and are widely believed to be a cellular basis of learning and memory (Bliss and Collingridge, 1993; Kirkwood et al., 1993).
The amygdala complex is well known as a key brain site for mood and
emotion (Rogan and LeDoux, 1996) and may also participate in seizures
(Mohapel et al., 1996). Furthermore, short-term and long-term synaptic
plasticity in the amygdala may play a critical role in conditioned fear
and anxiety (Davis et al., 1994; Maren and Fanselow, 1996) and in
kindling in which there are enduring pathological alterations in the
susceptibility to seizures (Kairiss et al., 1994). However, modulation
of synaptic transmission by activity-dependent processes has not yet
been well characterized in the amygdala. Although there have been
several reports of LTP in the amygdala, to date, LTD has not been
described in this structure (Maren, 1996).
In an attempt to better understand the cellular mechanisms that may
underlie the enduring changes in amygdala function associated with
amygdala-dependent neuropsychiatric disorders, we have characterized various forms of synaptic plasticity in the in vitro
amygdala slice. Neurons in the basolateral amygdala were synaptically
activated by electrical stimulation of the external capsule (EC) using
stimulation parameters and protocols similar to those in the in
vivo studies. Profound enduring changes in synaptic strength could
be induced. The nature of these changes depended on the stimulation
protocol. Notably, the direction of the long-term change in synaptic
efficacy induced by LFS was found to be dependent on the history of
previous activation. Ordinarily, NMDA receptor-independent enduring
synaptic potentiation was produced by LFS. However, when LFS was
preceded by an HFS train, the direction of the enduring change was
reversed to depression. This switch could be inhibited by the
presynaptic (group II) metabotropic glutamate receptor antagonist
2S--ethylglutamic acid (EGLU).
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MATERIALS AND METHODS |
Male Sprague Dawley rats weighing 75-150 gm were used. The rats
were decapitated, the brains were rapidly removed, and 500-µm-thick transverse slices of the amygdala were cut from tissue blocks with a
Vibroslice tissue slicer (Campden Instruments, Brunswick, ME). The
slices were placed in a beaker containing oxygenated artificial CSF
continuously bubbled at room temperature with 95% O2-5%
CO2 for at least 1 hr before use. The artificial CSF
contained (in mM): 117 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgCl2, 25 NaHCO3, and 11 glucose, and was bubbled with 95%
O2-5% CO2 to maintain a pH of 7.4.
For recording, slices were transferred to an interface chamber that was
continuously superfused with artificial CSF at a rate of 1-2 ml/min.
Microeletrodes were pulled from 1.0 mm microfiber-filled capillaries
using a Brown-flaming horizontal micropipette puller (Model P-80;
Sutter Instruments, San Rafael, CA). The resistance of the
microelectrodes when filled with 3 M KCl [or with 3 M KCl + 50 µM N-methyl bromide
quaternary salt (QX-314)] ranged from 80 to 130 M . The
microelectrode tips were visually positioned in the basolateral
subdivision of the amygdala using a binocular dissecting microscope.
Intracellular impalements were made in a blind manner. Recordings were
terminated if the resting potential was more positive than 55 mV or
if the action potential height was <70 mV.
Intracellular potentials were amplified with an Axoclamp-2A amplifier
(low pass filter, 3 KHz; Axon Instruments, Foster City, CA), and the
output was digitized with a Lab Master DMA TL-1 interface (Scientific
Solution, Solon, OH). On- and off-line data acquisition and analysis
were performed using SCAN version 4.2 (University of Strathclyde,
Glasgow, UK; www.strath.ac.uk/Departments/PhysPharm/ses.htm).
Synaptic responses were evoked with a bipolar stimulating electrode
(World Precision Instruments, Sarasota, FL) placed in the external
capsule ~2-3 mm from the recording site. Stimuli were delivered
using a Grass photoelectric stimulus isolation unit (PSIU6F; Astro-Med,
West Warwick, RI) having a constant current output. The stimulus
intensity was adjusted to produce a synaptic response 30-50% of
maximum amplitude without triggering an action potential. Single 0.1 msec duration monophasic pulses were applied continuously at 0.05 or
0.1 Hz throughout the experiment. HFS trains were 0.1 msec duration
pulses applied at 100 Hz for 1 sec; LFS trains were the same pulses
applied at 1 Hz for 15 min. Synaptic potentiation was defined as a
>20% increase in the average peak synaptic potential amplitude
elicited by six consecutive test stimuli. Synaptic potentiation
produced by HFS usually persisted <10 min. Because in this study we
wished to characterize the priming effect of HFS, in the few cases in
which the potentiation lasted longer than 10 min the experiment was not
included in the analysis.
Drugs were applied via the perfusion system of which the dead volume
was <0.2 ml. After solutions were switched, at least 8-10 min was
allowed for equilibration before testing. All chemicals and drugs were
obtained from Sigma (St. Louis, MO) except for D()-2-amino-5-phosphonopentanoic acid, (+)-dizocilpine
hydrogen maleate (MK-801), and lidocaine N-methyl bromide
quaternary salt (QX-314), which were from Research Biochemicals
International (Natick, MA), and EGLU and
(2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine (L-CCG1), which were from Tocris Cookson (St. Louis, MO).
All data are expressed as mean ± SEM. Statistical comparisons
were made with the t test.
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RESULTS |
External capsule (EC)-evoked synaptic responses in basolateral
amygdala neurons
Figure 1 (left)
schematically illustrates the positions of the stimulating electrode in
the external capsule and the recording electrode in the basolateral
amygdala. Intracellular recordings were performed from 72 basolateral
amygdala neurons. The mean resting potential was 65 ± 4 mV. At
resting potential, EC stimulation evoked short-latency depolarizing
synaptic responses that ranged in amplitude from 5 to 24 mV. The
stimulating current was adjusted so that the synaptic response was
<50% of maximum. As illustrated in Figure 1 (right),
synaptic responses were nearly completely blocked by perfusion with the
excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3-dione
(CNQX; 20 µM) and
D()-2-amino-5-phosphonopentanoate (APV; 100 µM).
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Figure 1.
Schematic representation of the brain slice
stimulation and recording configuration (left) and a
typical glutamate receptor-mediated excitatory synaptic response
(right). The sites of the intracellular recording
electrode in the basolateral amygdala (BLA) and the stimulating electrode in the external capsule (EC) are
shown. The synaptic response is transiently blocked by superfusion with 100 µM APV and 20 µM CNQX. The resting
membrane potential was 70 mV. In this and subsequent experiments, the
recording electrode contained 3 M KCl, except as
noted.
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Low-frequency stimulation (LFS) induces enduring
synaptic enhancement
As illustrated in Figures 2 and 4,
LFS (1 Hz for 15 min) induced an enduring enhancement of the synaptic
response. The enhancement began during the first 60 sec of stimulation
and progressively grew as the stimulation continued. The potentiated
synaptic response invariably persisted for >30 min after the
termination of LFS. In a series of eight experiments, the amplitude of
the potentiated synaptic response was 170 ± 14% of the baseline
value 30 min after the termination of LFS (see Fig. 4).
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Figure 2.
Low-frequency EC stimulation (LFS) induces
long-term potentiation (LTP) in a basolateral amygdala neuron.
A, Intracellularly recorded synaptic responses before,
during, and after LFS (1 Hz, 15 min; 900 pulses). Traces before
(a) and after (d, e) LFS are the
averages of six successive responses; traces during LFS
(b, c) are the averages of 60 responses.
B, Mean synaptic potential amplitudes as a percentage of
the amplitude at time 0; each data point represents the average of six
(during 0.1 Hz stimulation) or 60 (during LFS) successive responses.
LFS was applied during the 15 min period indicated by unfilled
arrows.
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LFS-induced enduring synaptic enhancement is NMDA
receptor independent
As illustrated in Figure 3, 100 µM APV did not alter the amplitude of the synaptic
response as assessed with test stimuli applied at 0.1 Hz. LFS in the
presence of APV produced an initial transient potentiation of the
synaptic potential amplitude followed by depression during the
remainder of the stimulation. After termination of the stimulus train,
there was a dramatic rebound to an enhanced level. A similar response
pattern was seen in five similar experiments (Fig.
4). In these experiments, the mean
synaptic potential amplitude 30 min after termination of LFS was
166 ± 19% of the initial baseline amplitude. In comparison the
synaptic potential amplitude at 30 min in eight control experiments was
170 ± 16%. There was no significant difference in the magnitude
of the potentiation between the control and APV experiments
(p > 0.05).
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Figure 3.
Effect of the NMDA receptor antagonist
D()-2-amino-5-phosphonopentanoate (APV; 100 µM) on LFS-induced LTP. A, Superimposed averaged synaptic responses before (a) and after
(b) (left) and before
(b) and during (c)
(right) LFS. Traces before and after LFS stimulation are
the averages of six successive responses; traces during LFS are the
averages of 60 responses. B, Mean synaptic potential
amplitudes as a percentage of the amplitude at time 0; each data point
represents the average of six (during 0.1 Hz stimulation) or 60 (during
LFS) successive responses. LFS (unfilled arrows) in the
presence of 100 µM APV produces an initial transient potentiation of the synaptic response amplitude followed by depression during the remainder of the stimulation. After termination of the LFS,
the synaptic response amplitude promptly rises to a persistent potentiated level.
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Figure 4.
Summary of data from experiments demonstrating the
failure of NMDA receptor blockade with APV to eliminate LFS-induced
enduring synaptic facilitation. The experimental protocols were similar to those of Figures 2 and 3. The plots present the
mean ± SEM of data from eight control experiments ( ) and five
experiments with 100 µM APV present during the period
indicated by the bar ( ). In each individual
experiment, amplitude values from 6 or 60 successive synaptic responses
were averaged during the 0.1 Hz test stimulation period or 1 Hz LFS
period, respectively. LTP of similar magnitude is induced by LFS
whether or not APV is present; however, in the presence of APV, there
is a transient reduction in synaptic response amplitude during the
period of LFS.
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High-frequency stimulation (HFS) induces NMDA receptor-dependent
short-term potentiation
Brief high-frequency stimulation (HFS; 100 Hz for 1 sec) induced a
marked enhancement in the synaptic response that persisted no longer
than 10 min in 38 of 44 cells examined (Fig.
5). In these 38 cells, the mean
potentiation was 252 ± 26% measured 1 min after the stimulus
train. In the remaining six cells, the potentiated response persisted
longer than 30 min; cells exhibiting such long-lasting potentiation in
response to HFS were not included further in the data analysis. As
illustrated in Figure 5B, after preincubation of the
amygdala slice with APV, the mean HFS-induced potentiation at 1 min was
136 ± 6% (n = 11), a 76% decrement from the
mean value obtained in the absence of APV.
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Figure 5.
Effects of the NMDA receptor antagonist APV on
short-term potentiation (STP). A, High-frequency
stimulation (HFS) (100 Hz; 1 sec; filled arrow) induces
a transient potentiation of the synaptic response lasting <10 min.
Each trace represents the average of six successive synaptic responses
evoked at 0.1 Hz. Numbers below traces indicate the
number of minutes after HFS. B, Time course of STP. Each
data point represents the mean ± SEM of the average synaptic
response amplitude values from 38 and 11 experiments in the absence
(control; ) and presence () of 100 µM APV, respectively. Note that in the presence of APV
the potentiated synaptic response amplitude decays to a level slightly
below baseline. APV was applied in the perfusion solution 10 min before
high-frequency stimulation.
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LFS after priming HFS induces enduring synaptic depression
We next examined how pairing HFS with LFS would affect synaptic
responses in the in vitro model system. In contrast to the situation in the naive slice in which LFS induced enduring synaptic facilitation, when LFS was applied 10 min after HFS (HFS/LFS) there was
a profound and long-lasting depression of the synaptic response. For
example, in the experiment of Figure 6,
the initial HFS produced the expected transient synaptic enhancement.
The subsequent LFS induced minimal facilitation followed by persistent synaptic depression. During the late synaptic depression, HFS again
produced transient synaptic facilitation, albeit of modestly reduced
magnitude. In nine similar experiments, there was 129 ± 4%
facilitation at 1 min after LFS onset and 74 ± 4% depression at
30 min after LFS termination. In this paradigm, depressed synaptic responses persisted as long as the recording could be maintained (up to
60 min).
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Figure 6.
Effects of conditioning HFS on the response to
LFS. A, Superimposed averaged synaptic responses before
(a) and after (b) HFS (left), before (c) and after
(d) (middle) LFS delivered 10 min after the HFS, and before (e) and after
(f) a second HFS delivered 30 min after
termination of the LFS. B, Mean response amplitudes as a
percentage of the amplitude at time 0; each data point represents the
average of six (during 0.1 Hz stimulation) or 60 (during LFS) successive responses. HFS (left filled arrow) induces an
initial transient potentiation. The subsequent LFS (unfilled
arrows) produces a small initial facilitation and enduring
synaptic depression. The depressed synaptic responses can be
transiently repotentiated by HFS (right filled
arrow).
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To examine the specificity of HFS for priming the response to LFS, we
examined whether LFS could serve as a priming stimulus for synaptic
depression. As illustrated in Figure 7, a
first presentation of LFS produced the expected enduring synaptic
facilitation. A second LFS train applied 30 min after termination of
the first failed to induce synaptic depression, indicating that LFS
cannot act as a priming stimulus in the same way that HFS does. This experiment also demonstrates that the LFS protocol used in these experiments yields a saturated facilitatory response inasmuch as the
second train produced no further facilitation. This observation was
confirmed in two additional experiments in which a second LFS train
applied 30 min after termination of the first failed to produce further
potentiation. In the three experiments, the initial LFS produced
182 ± 8% potentiation.
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Figure 7.
Effect of LFS on the response to a subsequent LFS
train. A, Superimposed averaged synaptic responses
before (a) and after (b) an
initial LFS train and before (c) and after
(d, e) a second LFS train applied 30 min after
termination of the first. Traces before and after LFS stimulation are
the averages of six successive responses. B, Mean
synaptic potential amplitudes as a percentage of the amplitude at time
0; each data point represents the average of six (during 0.1 Hz
stimulation) or 60 (during LFS) successive responses. LFS trains were
applied during the period marked by unfilled
arrows.
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Depotentiation of LFS-induced enduring synaptic enhancement
In a subsequent series of experiments, we sought to determine
whether HFS/LFS-induced synaptic depression could depotentiate synaptic
responses previously facilitated by LFS alone. A typical experiment is
shown in Figure 8. Application of LFS
induced the expected enduring synaptic facilitation, and the subsequent
presentation of HFS during the facilitated response caused further
transient potentiation. However, a second LFS train applied after the
priming HFS resulted in dramatic depotentiation of the facilitated
response. In three such experiments (including the one illustrated in
Fig. 8), the initial presentation of the LFS produced 187 ± 18%
potentiation of the synaptic response at 30 min after the LFS train. In
these cells, the second primed LFS train depotentiated the facilitated response by 75 ± 3% (p < 0.001). As is
typically observed in the absence of previous LFS potentiation (Figs.
6, 10), there was always a brief period of synaptic enhancement during
the LFS train before onset of the depotentiation.
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Figure 8.
Bidirectional control of synaptic strength by LFS
applied before or after HFS. A, Sample averaged synaptic
responses collected at various times during the experiment schematized
in B. In the naive cell (a-f),
LFS (open arrows in B) induces slow-onset
LTP. After HFS (filled arrow in
B), LFS induces enduring synaptic depression. Traces
before and after LFS stimulation are the averages of six successive
responses; traces during LFS are the averages of 60 responses.
B, Mean synaptic response amplitudes as a percentage of
the amplitude at time 0; each data point represents the average of six
(during 0.1 Hz stimulation) or 60 (during LFS) successive responses.
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HFS/LFS-induced synaptic depression occurs in the absence of a
change in cell input resistance
Cell input resistance was assessed by applying depolarizing or
hyperpolarizing current pulses through the recording electrode (Fig.
9A,B). As illustrated in
Figure 9C, there was no change in the current-voltage
relationship near resting potential during the period of
HFS/LFS-induced synaptic depression. Synaptic responses were increased
in amplitude with membrane hyperpolarization and decreased in amplitude
with depolarization. During HFS/LFS-induced synaptic depression, the
amplitude of the synaptic response was reduced at all membrane
potentials. The extrapolated reversal potential was near 0 mV, as
expected if the synaptic currents are carried by ionotropic excitatory
amino acid receptors (Fig. 1). HFS/LFS did not produce a change in the
reversal potential (fitted lines in Fig.
9D intersect abscissa at the same point).
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Figure 9.
HFS/LFS-induced synaptic depression occurs in the
absence of a change in input resistance. The experimental protocol
consisted of HFS followed 10 min later by LFS (see
scheme at top of A and B). A, Sample synaptic responses at
different membrane potentials evoked 10 min after HFS and before LFS.
Synaptic responses were recorded at the point indicated by the
filled arrow in the scheme of A. The
change in membrane potential was induced by depolarizing and
hyperpolarizing current steps injected through the recording electrode.
B, Sample synaptic responses at different membrane potentials after HFS/LFS. Synaptic responses were recorded at the point
indicated by the filled arrow in the scheme of
B (10 min after termination of LFS). The filled
triangles in A and B indicate the
onset of the test stimulus applied to the EC. C, Current-voltage relationships from the data presented in
A () and B (). Membrane potential
measurements were made at the end of the depolarizing current pulses.
The data points are connected by lines.
D, Relationship between the amplitude of the synaptic response and membrane potential in A and
B. The best straight line fits to the data points are
shown. Resting membrane potential was 75 mV. The electrode was filled
with 3 M KCl and 50 µM QX-314.
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HFS/LFS-induced synaptic depression is NMDA
receptor independent
To determine whether NMDA receptors play a role in HFS/LFS-induced
synaptic depression, a series of experiments were performed in which
100 µM APV was added to the perfusion solution 1 min after HFS but before the onset of LFS. Under these conditions, APV did
not affect the magnitude of the HFS-induced transient synaptic
potentiation. In six such experiments, APV failed to reduce the
magnitude of the synaptic depression, and in fact there was a
significant enhancement of the depression (p < 0.05) (Fig. 10). In an additional
experiment, a high concentration (10 µM) of the
uncompetitive NMDA receptor antagonist dizocilpine also did not
interfere with HFS/LFS-induced synaptic depression (Fig. 11). Taken together, these experiments
provide strong evidence that HFS/LFS-induced synaptic depression is not
mediated by NMDA receptor activation.
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Figure 10.
Effects of NMDA receptor blockade with APV on the
enduring synaptic depression induced by HFS/LFS. The experimental
protocol is schematized at the top of the figure. The
interval between HFS and LFS was 10 min. In the absence () and
presence () of 100 µM APV, LFS (open
arrows) induces an initial transient enhancement of the
synaptic response followed by enduring synaptic depression. With APV
(applied during the period indicated by the bar), the transient enhancement is reduced in magnitude, and the enduring synaptic depression is more pronounced. The data are presented as the
mean ± SEM from nine control experiments and six experiments with
APV. For each experiment, mean synaptic response amplitudes as a
percentage of the amplitude at time 0 were determined.
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Figure 11.
Effects of NMDA receptor blockade with
dizocilpine (MK-801) on the enduring synaptic depression induced by
HFS/LFS. Sample records are shown in A; the experimental
protocol is schematized in B, which also shows the time
course of the change in amplitude of the synaptic response. Traces
before (a-c) and after (e-g) LFS are
the averages of six successive responses; trace during LFS
(d) is the average of 60 responses. HFS
(left filled arrow) induces transient potentiation of
the synaptic response. After HFS and in the presence of 10 µM MK-801 (applied during period indicated by the
bar), LFS (open arrows) induces an
initial transient enhancement followed by enduring synaptic depression
similar to that obtained in the absence of MK-801 (Fig. 6). A
subsequent HFS train (right filled arrow) produces
transient potentiation of the depressed synaptic response.
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HFS-induced switch to synaptic depression is prevented by
2S--ethylglutamic acid (EGLU)
EGLU is a selective group II metabotropic glutamate receptor
antagonist that preferentially blocks presynaptic metabotropic glutamate receptors; the drug has little or no antagonist activity at
postsynaptic metabotropic and ionotropic glutamate receptors (Jane et
al., 1996). EGLU has been reported to inhibit the induction of
long-term depression in the rat hippocampus (Yokoi et al., 1996;
Manahan-Vaughan, 1997). Consequently, we examined whether HFS/LFS-induced enduring synaptic depression was sensitive to EGLU. By
itself, 50 µM EGLU did not affect the amplitude of
synaptic potentials (n = 3). In addition, the drug did
not alter LFS-induced enduring synaptic facilitation (n = 2). To confirm that EGLU is able to block group II metabotropic
glutamate receptors in the basolateral amygdala, we assessed whether it
could antagonize the depression of synaptic responses by the selective
group II metabotropic receptor agonist L-CCG1 (Conn and Pin, 1997). By itself, 50 µM L-CCG1 produced a 71 ± 11% reduction
in the synaptic response (n = 4). In the presence of 20 µM EGLU, the same concentration of L-CCG1 depressed
synaptic responses by only 12 ± 4% (n = 4; p < 0.001), confirming that EGLU acts as a group II
metabotropic glutamate receptor antagonist under our experimental
conditions. We next evaluated the effect of EGLU on the response to
HFS/LFS. When EGLU was applied during HFS/LFS, there was enduring
synaptic facilitation (Fig. 12), in
contrast to the synaptic depression ordinarily observed (Fig. 6). Note
in Figure 12 that the synaptic response amplitude decreases modestly
and transiently during the course of the LFS train. To determine
whether EGLU block of the switch to synaptic depression is attributable
to an action on the HFS priming mechanism per se or on the induction of
synaptic depression by the subsequent LFS, the drug was applied after
the termination of HFS but before LFS. Under these conditions, HFS/LFS induced persistent synaptic facilitation as illustrated in the experiment of Figure 13A,B.
In this experiment, the degree of facilitation fluctuates, as was
typically the case. Figure 13C summarizes data from five
similar experiments, confirming that in the presence of EGLU, HFS/LFS
fails to induce enduring synaptic depression.
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Figure 12.
2--Ethylglutamic acid (EGLU), a presynaptic
metabotropic glutamate receptor antagonist, inhibits the HFS-induced
switch from synaptic potentiation to synaptic depression.
A, Averaged synaptic responses before
(a) and after (b) HFS, and
before (c), during (d, e), and
after (f, g) LFS in the continuous presence of 50 µM EGLU. B, Mean synaptic response
amplitudes as a percentage of the amplitude at time 0; each data point
represents the average of six (during 0.1 Hz stimulation) or 60 (during
LFS) successive responses. HFS (filled arrow)
induces an initial transient potentiation, and the subsequent LFS
(unfilled arrows) induces enduring synaptic facilitation
instead of synaptic depression as obtained in the absence of EGLU
(compare, e.g., Fig. 6).
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Figure 13.
Application of EGLU after HFS but before LFS
inhibits the HFS-induced switch from synaptic potentiation to synaptic
depression. A, Averaged synaptic responses before
(a-c), during (d, c), and after
(f, g) LFS. B, Mean synaptic
response amplitudes as a percentage of the amplitude at time 0; each
data point represents the average of six (during 0.1 Hz stimulation) or
60 (during LFS) successive responses. HFS (filled
arrow) induces an initial transient potentiation. In the
presence of 50 µM EGLU, the subsequent LFS
(unfilled arrows) induces enduring synaptic facilitation
instead of synaptic depression as obtained in the absence of EGLU.
Fluctuations in the synaptic response amplitude after the stimulation
trains often occurred with this experimental protocol.
C, Summary of data from five experiments similar to that
of B. Each point represents the mean ± SEM.
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DISCUSSION |
The central observation in this study is that the direction of the
enduring change in synaptic efficacy induced by LFS in the amygdala can
be altered by the previous history of synaptic activity. Thus, in naive
basolateral amygdala slices, LFS induced enduring synaptic
potentiation. However, after priming HFS, there was persistent synaptic
depression. Neither of these processes required NMDA receptors,
although the switch from synaptic facilitation to depression may be
dependent on class II presynaptic metabotropic glutamate receptors.
In the hippocampus (Malenka, 1994; Bear and Abraham, 1996), cerebellum
(Linden and Connor, 1995), visual cortex (Artola et al., 1990),
striatum (Calabresi et al., 1997), and other brain regions (Artola and
Singer, 1993), the direction of stimulation-induced enduring changes in
synaptic strength often depends on the frequency and duration of
stimulation. Brief high-frequency stimulation typically results in a
long-lasting increase in synaptic strength, whereas prolonged
lower-frequency stimulation may cause persistent synaptic depression.
However, in the basolateral amygdala, we have found that the history of
synaptic activity, rather than the frequency, determines the direction
of the enduring modification in synaptic strength. Thus, homosynaptic
LTD could not be reliably elicited in naive pathways that had not been
transiently potentiated by previous HFS. However, synaptic weakening
was consistently induced in pathways that had undergone previous
HFS.
Several recent reports have described situations in which the history
of synaptic activation can alter stimulation-dependent long-term
synaptic plasticity (Manahan-Vaughan and Reymann, 1995; Thomas et al.,
1996). Indeed, the threshold for induction of both LTP and LTD can be
modified by previous afferent activity (Abraham and Tate, 1997). For
example, several laboratories have reported that a tetanic stimulus,
which by itself does not produce a long-term enhancement in synaptic
efficacy, may enable the subsequent induction of homosynaptic LTD in
the hippocampus (Collingridge et al., 1992; Wagner and Alger, 1995).
Such priming effects of synaptic activity on subsequent synaptic
plasticity in the hippocampus and cortex have recently been referred to
as "metaplasticity," a higher-order form of synaptic plasticity
(Abraham and Tate, 1997). In metaplasticity, synaptic activation does
not immediately result in an overt enduring change in synaptic
efficacy; rather, a persistent latent change occurs that alters the way
in which a subsequent synaptic stimulus induces synaptic plasticity.
The basolateral amygdala exhibits a novel form of metaplasticity in
which priming alters the direction of the change in synaptic strength
produced by repetitive, low-frequency synaptic activation. The capacity
of experience to alter the direction of activity-dependent synaptic
plasticity adds an extraordinary level of flexibility and complexity to
the ways in which LTP- and LTD-like mechanisms can persistently alter
the functional strength of synaptic connections. Further studies will
be needed to determine the conditions under which priming-induced
synaptic depression is invoked during behavior. Presumably, however,
this form of synaptic depression, like other forms of enduring synaptic weakening, provides a means of reducing the relative contribution of a
high activity synaptic input or, as illustrated by the experiment of
Figure 7, of depotentiating previously strengthened synaptic connections.
LFS-induced enduring synaptic enhancement in naive amygdala synapses
exhibits certain important differences from conventional LTP as is
typically studied in the hippocampal CA1 region and other brain areas
(Malenka, 1994; Bear and Abraham, 1996). First, LFS-induced synaptic
enhancement develops slowly in response to prolonged stimulation,
unlike conventional LTP in which synaptic enhancement is induced
immediately after a high-frequency stimulus train. Second, LFS-induced
synaptic enhancement in the basolateral amygdala occurs monotonically,
unlike conventional LTP that may develop in several phases. Third, in
contrast to the situation in the hippocampus in which LTP occludes
short-term potentiation (STP), in the amygdala LFS-induced synaptic
enhancement is additive with STP, suggesting that the two kinds of
synaptic potentiation are mediated by different mechanisms. Finally,
LFS-induced synaptic enhancement in the amygdala is not dependent on
NMDA receptors, in contrast to LTP in the CA1 hippocampus and several
other brain areas in which induction is dependent on NMDA receptors.
Thus, LFS-induced synaptic enhancement may have similarities with other forms of LTP that are not dependent on NMDA receptors, such as, for
example, in the hippocampal CA3 area (Zalutsky and Nicoll, 1990). In
addition, enduring synaptic depression as observed in the basolateral
amygdala after HFS/LFS exhibits differences from conventional LTD as
observed in the hippocampus. Most importantly, synaptic depression in
the amygdala can only be reliably induced when LFS occurs with a
previous history of HFS. Furthermore, in the hippocampus and other
brain areas, LTD is more readily induced in young animals than in older
animals (Bear and Malenka, 1994; Dudek and Friedlander, 1996). Clearly,
under the appropriate conditions, enduring synaptic depression can
occur at amygdala synapses in adult animals. Thus, synaptic plasticity
in the basolateral amygdala exhibits significant differences from
previously well characterized forms of synaptic plasticity in other
brain regions, and the underlying mechanisms will require further
study. In particular, the mechanism by which a high-frequency tetanus
that produces short-term facilitation can alter the response to
subsequent LFS remains to be determined. Our results lead to the
hypothesis that a final key event may be an alteration in the
sensitivity of presynaptic metabotropic glutamate receptors. Blockade
of presynaptic metabotropic glutamate receptors with EGLU eliminated
HFS/LFS-induced enduring synaptic depression and appeared to reveal an
underlying synaptic facilitation. One testable hypothesis to explain
this phenomenon is that presynaptic metabotropic glutamate receptors do
not normally contribute in a significant way to the regulation of
glutamate release under naive conditions but that HFS persistently
sensitizes these autoreceptors so that there is feedback inhibition of
release, resulting in synaptic depression. Thus we observed that EGLU
fails to alter the synaptic potential amplitude under basal conditions,
but it profoundly inhibits HFS/LFS-induced synaptic depression. Because in this model metabotropic glutamate receptors would participate in the
expression of HFS/LFS-induced synaptic depression but not in its
induction, this hypothesis is compatible with the observations that
EGLU blocks HFS/LFS-induced synaptic depression whether it is applied
throughout induction by HFS/LFS (experiment of Fig. 12) or only during
the expression phase evoked by LFS (experiments of Fig. 13).
In contrast to the NMDA receptor-independent enduring synaptic
facilitation obtained with LFS, HFS in naive or potentiated slices
reproducibly induced a robust, but usually short-lived, synaptic
enhancement that was strongly depressed by the application of the NMDA
receptor antagonist APV. In area CA1 of the hippocampus, tetanic
stimulation induces early decremental synaptic facilitation referred to
as short-term potentiation (STP), which precedes stable LTP (Malenka,
1994). The induction of both of these phases is dependent on NMDA
receptor activation; the magnitude of the postsynaptic NMDA
receptor-mediated Ca2+ increase appears to be a
critical variable controlling the duration of synaptic enhancement
(McGuinness et al., 1991). Short-term potentiation in the amygdala is
also dependent on NMDA receptor activation. However, it remains to be
determined whether the underlying mechanisms are similar to that in the
hippocampus.
Our observation that HFS can induce short-term but not in most cases
long-term synaptic enhancement is similar to that of Watanabe et al.
(1995, 1996) who found that high-frequency EC stimulation produced STP
but not LTP in the lateral amygdala under ordinary conditions.
Nevertheless, these authors did find that LTP could be induced by HFS
in the presence of GABAA receptor antagonists. Like the
enduring synaptic facilitation we observed with LFS, LTP in the lateral
amygdala evoked during GABA receptor blockade was NMDA receptor
independent (Watanabe et al., 1995). Similarly, Chapman and Bellavance
(1992) reported that LTP could be induced in the basolateral amygdala
in the presence of GABA receptor blockade. These authors also concluded
that activation of NMDA receptors was not required.
Although we and others failed to obtain LTP in most basolateral
amygdala neurons with high-frequency tetanic EC stimulation, it may be
possible to obtain LTP in this structure with HFS of other input
pathways, and the LTP so induced may be NMDA receptor dependent. Gean
et al. (1993) reported that HFS of the ventral endopyriform nucleus in
an in vitro slice preparation could induce NMDA
receptor-dependent LTP in the basolateral amygdala. Similarly, Maren
and Fanselow (1995) have observed that prolonged HFS of the ventral
angular bundle in the rat in vivo induced enduring, NMDA
receptor-dependent LTP in the same structure. Thus, the extent to which
NMDA receptors participate in stimulus-evoked synaptic plasticity is
dependent on the input pathway. Interestingly, in our experiments, APV
transiently depressed the LFS-induced synaptic depolarization (Fig. 4),
indicating that NMDA receptor activation may contribute to the synaptic
response to EC stimulation despite the fact that NMDA receptors do not
seem to be required for induction of the persistent synaptic
enhancement.
The participation of the amygdala complex in affective and motivational
aspects of behavior, and in particular in Pavlovian fear conditioning,
is now well established (Davis et al., 1994; Gallagher and Holland,
1994; Cahill et al., 1995; Maren and Fanselow, 1996). The unique forms
of synaptic plasticity described here could play a role in the
formation, storage, and extinction of these behavioral functions. In
particular, because LTP in the basolateral amygdala may serve as a
substrate for fear conditioning (Maren and Fanselow, 1996), it is
conceivable that HFS/LFS-induced enduring synaptic depression could
participate in some aspects of the extinction of conditioned fear. It
has been proposed that post-traumatic stress disorder (PTSD) may
represent a form of conditioned fear in which there is a failure of
extinction mechanisms (Charney et al., 1993). If this is the case,
strategies that promote enduring synaptic depression could be of use
therapeutically. In fact, there is emerging evidence that a form of LFS
(administered by transcranial magnetic stimulation) may be of value in
PTSD (McCann et al., 1998). A tantalizing consideration is whether HFS/LFS-induced synaptic depression may play a role in the clinical improvement. Whether a similar approach could be useful in epilepsy therapy remains to be determined.
In conclusion, the present study provides the first demonstration of
stimulus-dependent enduring synaptic depression in the amygdala. In
contrast to the situation in some other brain regions in which LTD is
produced by homosynaptic LFS, in the EC-basolateral amygdala circuit,
enduring synaptic depression occurred only when LFS was preceded by a
high-frequency priming stimulus. Further studies are required to define
the range of stimulation protocols and parameters that can evoke this
novel form of synaptic plasticity. These details will be critical in
understanding the role of this plasticity mechanism in health and
disease.
| |
FOOTNOTES |
Received Sept. 16, 1997; revised Dec. 10, 1997; accepted Dec. 12, 1997.
H.L. gratefully acknowledges the support of the Stanley Foundation and
Drs. N. Bradley Keele and Patricia Shinnick-Gallagher for advice
regarding the amygdala slice preparation.
Correspondence should be addressed to Dr. Michael A. Rogawski, National
Institute of Neurological Disorders and Stroke, National Institutes of
Health, Building 10, Room 5N-250, 10 Center Drive MSC 1408, Bethesda,
MD 20892-1408.
| |
REFERENCES |
-
Abraham WC,
Tate WP
(1997)
Metaplasticity: a new vista across the field of synaptic plasticity.
Prog Neurobiol
52:303-323[Web of Science][Medline].
-
Artola A,
Singer W
(1993)
Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation.
Trends Neurosci
16:480-487[Web of Science][Medline].
-
Artola A,
Brocher S,
Singer W
(1990)
Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex.
Nature
347:69-72[Medline].
-
Bear MF
(1996)
Progress in understanding NMDA-receptor-dependent synaptic plasticity in the visual cortex.
J Physiol (Paris)
90:223-227[Web of Science][Medline].
-
Bear MF,
Abraham WC
(1996)
Long-term depression in hippocampus.
Annu Rev Neurosci
19:437-462[Web of Science][Medline].
-
Bear MF,
Malenka RC
(1994)
Synaptic plasticity: LTP and LTD.
Curr Opin Neurobiol
4:389-399[Medline].
-
Bliss TV,
Collingridge GL
(1993)
A synaptic model of memory: long-term potentiation in the hippocampus.
Nature
361:31-39[Medline].
-
Cahill L,
Babinsky R,
Markowitsch HJ,
McGaugh JL
(1995)
The amygdala and emotional memory.
Nature
377:295-296[Medline].
-
Calabresi P,
Pisani A,
Centonze D,
Bernardi G
(1997)
Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum.
Neurosci Biobehav Rev
21:519-523[Web of Science][Medline].
-
Chapman PF,
Bellavance LL
(1992)
Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation.
Synapse
11:310-318[Web of Science][Medline].
-
Charney DS,
Deutch AY,
Krystal JH,
Southwick SM,
Davis M
(1993)
Psychobiologic mechanisms of posttraumatic stress disorder.
Arch Gen Psychiatry
50:294-305[Abstract/Free Full Text].
-
Collingridge GL,
Randall AD,
Davies CH,
Alford S
(1992)
The synaptic activation of NMDA receptors and Ca2+ signalling in neurons.
Ciba Found Symp
164:162-171[Medline].
-
Conn PJ,
Pin JP
(1997)
Pharmacology and functions of metabotropic glutamate receptors.
Annu Rev Pharmacol Toxicol
37:205-237[Web of Science][Medline].
-
Davis M,
Rainnie D,
Cassell M
(1994)
Neurotransmission in the rat amygdala related to fear and anxiety.
Trends Neurosci
17:208-214[Web of Science][Medline].
-
Dudek SM,
Bear MF
(1993)
Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus.
J Neurosci
13:2910-2918[Abstract].
-
Dudek SM,
Friedlander MJ
(1996)
Developmental down-regulation of LTD in cortical layer IV and its independence of modulation by inhibition.
Neuron
16:1097-1106[Web of Science][Medline].
-
Gallagher M,
Holland PC
(1994)
The amygdala complex: multiple roles in associative learning and attention.
Proc Natl Acad Sci USA
91:11771-11776[Abstract/Free Full Text].
-
Gean PW,
Chang FC,
Huang CC,
Lin JH,
Way LJ
(1993)
Long-term enhancement of EPSP and NMDA receptor-mediated synaptic transmission in the amygdala.
Brain Res Bull
31:7-11[Web of Science][Medline].
-
Heynen AJ,
Abraham WC,
Bear MF
(1996)
Bidirectional modification of CA1 synapses in the adult hippocampus in vivo.
Nature
381:163-166[Medline].
-
Jane DE,
Thomas NK,
Tse HW,
Watkins JC
(1996)
Potent antagonists at the L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord.
Neuropharmacology
35:1029-1035[Web of Science][Medline].
-
Kairiss EW,
Racine RJ,
Smith GK
(1984)
The development of the interictal spike during kindling in the rat.
Brain Res
322:101-110[Web of Science][Medline].
-
Kirkwood A,
Dudek SM,
Gold JT,
Aizenman CD,
Bear MF
(1993)
Common forms of synaptic plasticity in the hippocampus and neocortex in vitro.
Science
260:1518-1521[Abstract/Free Full Text].
-
Linden DJ,
Connor JA
(1995)
Long-term synaptic depression.
Annu Rev Neurosci
18:319-357[Web of Science][Medline].
-
Malenka RC
(1994)
Synaptic plasticity in the hippocampus: LTP and LTD.
Cell
78:535-538[Web of Science][Medline].
-
Manahan-Vaughan D
(1997)
Group 1 and 2 metabotropic glutamate receptors play differential roles in hippocampal long-term depression and long-term potentiation in freely moving rats.
J Neurosci
17:3303-3311[Abstract/Free Full Text].
-
Manahan-Vaughan D,
Reymann KG
(1995)
1S,3R-ACPD dose-dependently induces a slow-onset potentiation in the rat hippocampal CA1 region in vivo.
Neuropharmacology
34:1103-1105[Web of Science][Medline].
-
Maren S
(1996)
Synaptic transmission and plasticity in the amygdala: an emerging physiology of fear conditioning circuits.
Mol Neurobiol
13:1-22[Web of Science][Medline].
-
Maren S,
Fanselow MS
(1995)
Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo.
J Neurosci
15:7548-7564[Abstract].
-
Maren S,
Fanselow MS
(1996)
The amygdala and fear conditioning: has the nut been cracked?
Neuron
16:237-240[Web of Science][Medline].
-
McCann UD, Kimbrell TA, George MS, Danielson AL, Herscovitch P, Hallett
M, Post RM (1998) Repetitive transcranial magnetic
stimulation for posttraumatic stress disorder: two case reports. Arch
Gen Psychiatry, in press.
-
McGuinness N,
Anwyl R,
Rowan M
(1991)
The effects of external calcium on the N-methyl-D-aspartate induced short-term potentiation in the rat hippocampal slice.
Neurosci Lett
131:13-16[Web of Science][Medline].
-
Mohapel P,
Dufresne C,
Kelly ME,
McIntyre DC
(1996)
Differential sensitivity of various temporal lobe structures in the rat to kindling and status epilepticus induction.
Epilepsy Res
23:179-187[Web of Science][Medline].
-
Mulkey RM,
Malenka RC
(1992)
Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus.
Neuron
9:967-975[Web of Science][Medline].
-
Post RM, Silberstein SD (1994) Shared mechanisms in affective
illness, epilepsy, and migraine. Neurology 44[Suppl 7]:S37-S47.
-
Rogan MT,
LeDoux JE
(1996)
Emotion: systems, cells, synaptic plasticity.
Cell
85:469-475[Web of Science][Medline].
-
Thomas MJ,
Moody TD,
Makhinson M,
O'Dell TJ
(1996)
Activity-dependent
 -adrenergic modulation of low frequency stimulation induced LTP in the hippocampal CA1 region.
Neuron
17:475-482[Web of Science][Medline]. -
Wagner JJ,
Alger BE
(1995)
GABAergic and developmental influences on homosynaptic LTD and depotentiation in rat hippocampus.
J Neurosci
15:1577-1586[Abstract].
-
Watanabe Y,
Ikegaya Y,
Saito H,
Abe K
(1995)
Roles of GABAA, NMDA and muscarinic receptors in induction of long-term potentiation in the medial and lateral amygdala in vitro.
Neurosci Res
21:317-322[Web of Science][Medline].
-
Watanabe Y,
Ikegaya Y,
Saito H,
Abe K
(1996)
Opposite regulation by the -adrenoceptor-cyclic AMP system of synaptic plasticity in the medial and lateral amygdala in vitro.
Neuroscience
71:1031-1035[Web of Science][Medline].
-
Yokoi M,
Kobayashi K,
Manabe T,
Takahashi T,
Sakaguchi I,
Katsuura G,
Shigemoto R,
Ohishi H,
Nomura S,
Nakamura K,
Nakao K,
Katsuki M,
Nakanishi S
(1996)
Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2.
Science
273:645-647[Abstract].
-
Zalutsky RA,
Nicoll RA
(1990)
Comparison of two forms of long-term potentiation in single hippocampal neurons.
Science
248:1619-1624[Abstract/Free Full Text].
Copyright © 1998 Society for Neuroscience 0270-6474/98/1851662-09$05.00/0
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Top
Abstract
Introduction
