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The Journal of Neuroscience, September 1, 2001, 21(17):6889-6896
Intra-Amygdala Blockade of the NR2B Subunit of the NMDA Receptor
Disrupts the Acquisition But Not the Expression of Fear
Conditioning
Sarina M.
Rodrigues,
Glenn E.
Schafe, and
Joseph E.
LeDoux
W. M. Keck Foundation Laboratory of Neurobiology, Center for
Neural Science, New York University, New York, New York 10003
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ABSTRACT |
The lateral nucleus of the amygdala (LA) is an essential component
of the neural circuitry underlying Pavlovian fear conditioning. Although blockade of NMDA receptors in LA and adjacent areas
before training disrupts the acquisition of fear conditioning, blockade before testing also often disrupts the expression of fear responses. With this pattern of results, it is not possible to distinguish a
contribution of NMDA receptors to plasticity from a role in synaptic
transmission. In past studies, NMDA blockade has been achieved using
the antagonist
D,L-2-amino-5-phosphovalerate, which blocks the entire heteromeric receptor complex. The present experiments examined the effects of selective blockade of the NR2B subunit of the
NMDA receptor in LA using the selective antagonist ifenprodil. Systemic
injections of ifenprodil before training led to a dose-dependent impairment in the acquisition of auditory and contextual fear conditioning, whereas injections before testing had no effect. Intra-amygdala infusions of ifenprodil mirrored these results and, in
addition, showed that the effects are attributable to a
disruption of fear learning rather than a disruption of memory consolidation. NMDA receptors in LA are thus involved in fear conditioning, and the NR2B subunit appears to make unique contributions to the underlying plasticity.
Key words:
fear; learning; amygdala; NMDA receptor; NR2B subunit; ifenprodil
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INTRODUCTION |
The lateral nucleus of the amygdala
(LA) is an essential component of the neural circuit underlying
Pavlovian fear conditioning and also appears to be a crucial site of
plasticity in this circuitry (Fanselow and LeDoux, 1999 ; LeDoux, 2000).
Nevertheless, the synaptic mechanisms in LA mediating fear conditioning
remain controversial.
Building on the role of NMDA receptors in long-term synaptic
potentiation (LTP) in the CA1 region of the hippocampus (for review,
see Bliss and Collingridge, 1993; Malenka and Nicoll, 1999), a number
of studies have assessed whether blockade of NMDA receptors in LA and
adjacent areas, especially the basal nucleus (B), would interfere with
fear conditioning (Miserendino et al., 1990; Campeau et al., 1992;
Fanselow and Kim, 1994; Lee and Kim, 1998). These studies have
consistently found that blockade of NMDA receptors in LA and B before
training prevents the acquisition of fear conditioning, suggesting that
NMDA receptors mediate synaptic plasticity during learning. However,
several of these studies have also found that NMDA receptor blockade
before testing prevents the expression of previously conditioned
responses (Maren et al., 1996; Lee and Kim, 1998; Lee et al., 2001).
These observations suggest that the effects of NMDA blockade on
acquisition could be attributable to a disruption of routine synaptic
transmission instead of, or in addition to, a disruption of plasticity.
Indeed, a number of reports have demonstrated the involvement of NMDA receptors in routine synaptic transmission in LA and B (Li et al.,
1995, 1996; Maren, 1996; Weisskopf and LeDoux, 1999). Collectively, this pattern of findings makes it difficult to accept the conclusion that NMDA blockade during learning only disrupts plasticity.
NMDA receptors are heteromeric complexes composed of several subunits
(Nakanishi, 1992; Hollmann and Heinemann, 1994). The NR1 subunit is
required for channel function, whereas certain NR2 subunits, especially
the NR2A and NR2B subunits, regulate channel gating (Moyner et al.,
1992). Past studies of fear conditioning have used the NMDA antagonist
D,L-2-amino-5-phosphovalerate (APV), which
disrupts the entire receptor complex (Watkins and Olverman, 1987).
Thus, it might be possible to disrupt acquisition but not expression of
fear conditioning by using an antagonist with partial and selective
effects on individual channel subunits. In vitro studies
have shown that the NR1-NR2B complex exhibits longer EPSPs than the
NR1-NR2A complex (Moyner et al., 1994), allowing a longer time window
for coincidence detection in the former. Given that coincidence
detection is believed to be an important function performed by NMDA
receptors during learning (Tsien, 2000), the NR2B subunit may be
especially important during plasticity. Indeed, during early
development, a time during which much plasticity occurs, the NR2B
subunit is especially prevalent (Sheng et al., 1994; Portera-Cailliau
et al., 1996). Furthermore, tyrosine phosphorylation of NR2B has been
correlated with both synaptic plasticity in the hippocampus and taste
learning in the insular cortex (Rosenblum et al., 1996, 1997; Rostras
et al., 1996), and transgenic overexpression of the NR2B subunit in
mice enhances learning in several tasks, including fear conditioning
(Tang et al., 1999). In the present study we therefore examined whether
ifenprodil, a selective antagonist of the NR2B subunit (Chenard and
Menniti, 1999), would disrupt the acquisition but not the expression of
fear conditioning in rats. We first tested this with systemic
injections of ifenprodil and then turned to infusions targeted to LA.
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MATERIALS AND METHODS |
Subjects. Subjects were adult male Sprague Dawley
rats (Hilltop Laboratories, Scottdale, PA). They were housed
individually in plastic Nalgene cages and placed on a 12 hr light/dark
cycle. Food and water were provided ad libitum throughout
the experiment. All procedures were in accordance with the National
Institutes of Health Guide for the Care and Use of Experimental
Animals and were approved by the New York University Animal Care
and Use Committee.
Surgery. Rats were anesthetized with a mixture of ketamine
(100 mg/kg, i.p.; Ketaset; Phoenix, St. Joseph, MO), xylazine (6.0 mg/kg, i.p.; Xyla-Jet; Phoenix), and medetomidine (0.5 mg/kg, i.p.;
Domitor; Pfizer, New York, NY). Using a stereotaxic apparatus, guide
cannulas (22 gauge; Plastics One, Roanoke, VA) fitted with internal
cannulas that extended out 1.5 mm from the base of the guide were
positioned just above LA using the following coordinates from Paxinos
and Watson (1986): 2.8 mm posterior to bregma, 5.3 mm lateral to the
midline, and 8.0 mm ventral to the skull surface. The guide cannulas
were fixed to screws in the skull with dental cement. Internal cannulas
were replaced with dummy cannulas, cut 0.5 mm longer than the guide
cannulas, to prevent clogging. After surgery, rats were administered
butorphanol tartrate (2.0 mg/kg, i.p.; Torbugesic; Fort Dodge
Laboratories, Fort Dodge, IA) and atipamezole (1.0 mg/kg, i.p.;
Antisedan; Pfizer, New York, NY) for analgesia and reversal of the
anesthetic. Rats were given at least 5 d to recover before
experimental procedures.
Drug administration. For experiments testing the effects of
ifenprodil via systemic administration, rats were given intraperitoneal injections. Ifenprodil (Sigma, St. Louis, MO) was dissolved in vehicle
(0.1 M PBS, 0.1% tartaric acid) at varying
concentrations to obtain a constant injection volume of ~2.5 ml/kg
for each rat. This was done to keep the amount of solution injection
constant to control for potential effects of the vehicle alone.
Injections of vehicle or drug solution were given 15 min before
conditioning and testing.
In studies involving intra-amygdala infusions, rats were held gently in
the experimenter's lap while dummy cannulas were exchanged with 28 gauge infusion cannulas. The cannulas were connected to 1.0 µl
Hamilton syringes via polyurethane tubing. The tubing was back-filled
with sesame oil, with a small air bubble separating the oil from the
drug solution. Drugs were infused bilaterally with an infusion pump at
a rate of 0.25 µl/min. A total volume of 0.5 µl of an ifenprodil
drug solution or vehicle (0.1 M PBS, 0.1% tartaric
acid) was infused into each amygdala. After infusion, the cannulas were
left in place for an additional 1 min to allow the solution to diffuse
away from the cannula tip. The dummy cannulas were then replaced and
the rat was returned to its home cage. Infusions occurred 15-30 min
before conditioning and testing.
Apparatus. Pavlovian fear conditioning took place in a
Plexiglas conditioning chamber with a metal grid floor (model E10-10; Coulbourn Instruments, Lehigh Valley, PA), dimly lit with a single house light and enclosed within a sound-attenuating chamber (model E20). Testing for auditory fear conditioning occurred in a distinct Plexiglas chamber (ENV-001; MedAssociates, Georgia, VT) to minimize generalization from the conditioning environment. The tone testing chamber was brightly lit with three house lights and contained a black
Formica floor that had been washed with a peppermint soap. A
microvideocamera mounted at the top of the chambers allowed videotaping
during auditory fear testing for later scoring. Testing for contextual
conditioning took place in the same chamber as fear conditioning.
Fear conditioning procedure. On the day before conditioning
(day 1), rats were habituated to the training and testing chambers for
a minimum of 10-15 min. Habituation was counterbalanced between groups
to control for possible order effects. On the day of conditioning (day
2), rats were injected with drug or vehicle and given 2-3 min to
acclimate to the conditioning chamber. This was followed by the
presentation of five pairings of a 20 sec tone conditioned stimulus (CS) (5 kHz, 75 dB) that coterminated with a foot shock unconditioned stimulus (US) (0.5 sec, 0.5 mA). The intertrial interval
(ITI) varied randomly between 90 and 120 sec. After conditioning, rats
were returned to their home cages and to the colony.
To assess possible effects of ifenprodil on shock sensitivity, rats
were observed throughout the training procedure. No differences in
reactivity to the shock US were observed. Rats were observed to run,
jump, and/or vocalize normally to the shock (our unpublished observations).
Testing of conditioned fear responses. Approximately 24 hr
after conditioning, long-term memory (LTM) of fear responses
conditioned to the tone CS and the conditioning apparatus (context)
were separately tested. Responses conditioned to the tone CS were
measured in the novel test chamber (see above). After a brief
acclimation period to the test chamber, the rats received five test
tones (20 sec, 5 kHz, 75 dB; ITI, 100 sec). Then, they were placed in the conditioning chamber and allowed to explore for 5 min to allow them
time to recognize the context, after which the duration of freezing was
measured every other 30 sec for an additional 5 min. Testing for
tone and contextual memory was counterbalanced within groups to control
for possible order effects.
In some studies, an additional test of short-term memory (STM) was
performed 1 hr after fear conditioning. Conditioning to the tone and
context were separately assessed, as described above, and as before the
order of the tone and context was counterbalanced. In the STM test of
conditioning to the tone, only three test tones were used to minimize
extinction. The context and tone STM tests were approximately the same
total length (10 min).
Histology. To verify injector tip location in the
intra-amygdala infusion experiments, rats were anesthetized with an
overdose of chloral hydrate (600 mg/kg, i.p.) and perfused
transcardially with 10% buffered formalin. The brains were post-fixed
in 30% sucrose in 10% buffered formalin and subsequently blocked,
sectioned on a cryostat or microtome at 50 µm, and stained for Nissl
with thionin. Sections were coverslipped with Permount and examined under light microscopy for injector tip penetration into the amygdala.
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RESULTS |
We first determined whether systemic administration of the NR2B
antagonist ifenprodil would affect the acquisition and/or expression of
fear conditioning. This study was then repeated with infusions of
ifenprodil through cannulas targeted for LA. The intra-amygdala study
was subsequently replicated with the addition of a test of STM to
determine whether NR2B receptor blockade in the amygdala prevents the
learning or the consolidation of fear conditioning. For each series of
experiments, freezing scores across trials did not significantly differ
and were therefore averaged for each rat into a single score. Scores
were then expressed as a percentage of total CS presentation or
observation time. All data were analyzed using ANOVA and Duncan's
multiple range post hoc t tests.
Systemic injections of ifenprodil
In the first series of experiments, separate groups of rats were
given injections of vehicle or one of three doses of ifenprodil (1.0, 3.0, or 10.0 mg/kg, i.p.) either before training or before a testing
session that took place ~24 hr after training (for a total of eight
groups). Animals in the pretraining infusion groups received either
ifenprodil or vehicle immediately before fear conditioning and then
received vehicle injections immediately before testing. Animals in the
pretesting infusion groups received vehicle injections before training
and then received one of the doses of ifenprodil or vehicle immediately
before testing.
Pretraining injections
Pretraining injections of ifenprodil produced a dose-dependent
decrease in the amount of freezing elicited by the tone CS (Fig.
1A). The ANOVA showed a
significant effect for group (F(3,30) = 20.68; p < 0.01), and post hoc t tests
showed a significant difference between the vehicle and each of the
ifenprodil groups, as well as between the group that received the
highest dose of ifenprodil compared with groups that received the lower
doses (p < 0.05). The contextual memory test
led to a similar pattern of results. The ANOVA for contextual memory
scores showed a significant effect for group
(F(3,30) = 8.93; p < 0.001), and post hoc t tests showed a significant difference
between the vehicle and ifenprodil groups for observation periods
(p < 0.01).
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Figure 1.
Effects of systemic injections of ifenprodil on
LTM. A, Top, Outline of general
behavioral procedures for pretraining systemic intraperitoneal
injections of ifenprodil. Bottom, Mean (±SE) percentage
freezing for tone and contextual LTM in rats injected with vehicle
(n = 10), 1.0 mg/kg ifenprodil
(n = 8), 3.0 mg/kg ifenprodil
(n = 8), or 10.0 mg/kg ifenprodil
(n = 8) before training. B,
Top, Outline of general behavioral procedures for
pretesting systemic intraperitoneal injections of ifenprodil.
Bottom, Mean (±SE) percentage freezing for tone and
contextual LTM in rats injected with vehicle (n = 10), 1.0 mg/kg ifenprodil (n = 8), 3.0 mg/kg
ifenprodil (n = 8), or 10.0 mg/kg ifenprodil
(n = 8) before testing. *p < 0.05 relative to vehicle.
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Pretesting injections
Ifenprodil injections before testing produced a different pattern
of results (Fig. 1B). For tone memory, the ANOVA
revealed a significant effect for group
(F(3,30) = 87.03; p < 0.01), but post hoc t tests showed that this
effect was due only to impairments in the highest dose group
(p < 0.01). The other two doses, each of which
significantly impaired acquisition, had no effect on the expression of
previously conditioned auditory fear (p > 0.05). The ANOVA for contextual memory scores also showed an effect
(F(3,30) = 59.83; p < 0.01). However, as in the auditory test, this effect was observed only
in the group receiving the highest dose (p < 0.05). As before, the two lower doses of ifenprodil, which were effective at blocking the acquisition of contextual fear, failed to
block expression (p > 0.05). Thus, doses of
ifenprodil sufficient to block acquisition of fear conditioning have no
effect on performance. Only the highest dose affected both acquisition
and performance.
Intra-amygdala infusions of ifenprodil
To determine whether the effects of systemic administration of
ifenprodil might be attributable to an action in LA, rats were prepared
with bilateral cannula implants aimed for LA. After recovery, separate
groups of rats received local infusions of ifenprodil (1.0 or 0.1 µg)
or vehicle either before training or before testing using the same
basic design as in the systemic study above.
Pretraining injections
Ifenprodil infusion before conditioning produced a dose-dependent
impairment in freezing for both tone and context memory (Fig.
2A). The ANOVA for tone
memory scores showed a significant effect for group
(F(2,21) = 120.3; p < 0.001), and post hoc t tests showed that the two
ifenprodil groups differed from the vehicle group
(p < 0.01). Furthermore, less freezing occurred in the high-dose group than in the low-dose group
(p < 0.05), indicating a dose-dependent effect
of ifenprodil in LA. In the test of contextual conditioning,
pretraining infusions also produced a significant effect for group
(F(2,21) = 62.55; p < 0.001), and post hoc t tests again showed that
the two ifenprodil groups froze significantly less than the vehicle
group (p < 0.01).
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Figure 2.
Effects of intra-amygdala infusions of ifenprodil
on LTM. A, Top, Outline of general
behavioral procedures for pretraining intra-amygdala infusions of
ifenprodil for LTM testing only. Bottom, Mean (±SE)
percentage freezing for tone and contextual LTM in rats given bilateral
intra-amygdala infusions of vehicle (n = 10), 0.1 µg of ifenprodil (n = 6), or 1.0 µg of
ifenprodil (n = 8) before training.
B, Top, Outline of general behavioral
procedures for pretesting intra-amygdala infusions of ifenprodil for
LTM testing only. Bottom, Mean (±SE) percentage
freezing for tone and contextual LTM in rats given bilateral
intra-amygdala infusions of vehicle (n = 10), 0.1 µg of ifenprodil (n = 6), or 1.0 µg of
ifenprodil (n = 8) before testing. *p < 0.05 relative to vehicle.
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Pretesting injections
Intra-amygdala infusions before testing did not produce a
significant impairment in freezing for either tone or contextual conditioning (Fig. 2B). The ANOVA for either test
showed no significant effects for group (p > 0.05). Thus, consistent with the findings of the experiments using
systemic administration, intra-amygdala infusion of ifenprodil impairs
acquisition but not expression of fear conditioning.
Effects of intra-amygdala infusions of ifenprodil on short-term
versus long-term memory
In the studies described above, pretraining infusions of
ifenprodil led to a failure to form a LTM of fear conditioning, as assessed 24 hr after training. This deficit could be caused by a
failure to learn during acquisition or a failure to consolidate learning in the time after training. To distinguish between these alternatives, we repeated the intra-amygdala study with the addition of
a test of STM shortly after training. In this design, the rats again
received vehicle or drug either before training or before a test
session 24 hr after training, but in addition all rats received vehicle
or drug infusions immediately before a STM test that took place 1 hr
after training (Fig. 3).
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Figure 3.
Effects of intra-amygdala infusions of ifenprodil
on STM and LTM. A, Top, Outline of
general behavioral procedures for pretraining intra-amygdala infusions
of ifenprodil for STM testing followed by LTM testing.
Bottom, Mean (±SE) percentage freezing for tone
(left) and contextual (right) STM
and LTM in rats given bilateral intra-amygdala infusions of vehicle
(n = 8), 0.1 µg of ifenprodil
(n = 6), or 1.0 µg of ifenprodil
(n = 8) before training. B,
Top, Outline of general behavioral procedures for
pretesting intra-amygdala infusions of ifenprodil for STM testing
followed by LTM testing. Bottom, Mean (±SE) percentage
freezing for tone (left) and contextual
(right) STM and LTM in rats given bilateral
intra-amygdala infusions of vehicle (n = 8), 0.1 µg of ifenprodil (n = 6), or 1.0 µg of
ifenprodil (n = 8) before testing. *p < 0.05 relative to vehicle.
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Pretraining infusions
Rats receiving pretraining infusions of ifenprodil showed impaired
STM for both the tone CS and context when tested 1 hr after training,
indicating that they failed to learn (Fig. 3A). The ANOVA
for tone STM scores showed a significant effect for group (F(2,19) = 69.94; p < 0.01), and post hoc t tests showed a significant difference between the vehicle and ifenprodil groups. Both doses of
ifenprodil infused into the amygdala before conditioning induced a
pronounced deficit on acquisition compared with controls
(p < 0.01). The STM data in the context test
displayed a similar pattern. The ANOVA showed a significant effect for
group (F(2,19) = 53.86;
p < 0.001), and post hoc t tests
revealed that the low and high doses of ifenprodil produced a
significant decrease in freezing behavior (p < 0.03) compared with vehicle controls.
Intra-amygdala infusion of ifenprodil before training also produced a
dose-dependent impairment in the LTM of auditory and contextual
fear when tested 24 hr after training. The ANOVA for tone LTM scores
revealed a significant effect for group
(F(2,19) =18.34; p < 0.01). Compared with controls, post hoc t tests revealed both doses of ifenprodil induced an impairment in freezing
(p < 0.05). A similar pattern was found for
contextual conditioning, in which the ANOVA showed a significant effect
for group (F(2,19) = 6.74;
p < 0.03), and t tests showed that both
doses of ifenprodil caused a deficit in contextual fear conditioning
(p < 0.05). Thus, intra-amygdala infusions of
ifenprodil impair both STM and LTM of fear conditioning, which is
consistent with an effect on acquisition rather than on processes
related to consolidation.
The vehicle infused controls exhibited somewhat less freezing to the
tone CS and context in the LTM test than the vehicle controls in the
previous experiment in which there was no STM test inserted between
training and LTM testing. This is likely attributable to the occurrence
of some fear extinction during the STM test trials in which the
subjects were exposed to the CS and context in the absence of the US.
Still, the effects of intra-amygdala infusions had a similar effect on
LTM as in the previous experiments (Fig. 3A).
Pretesting infusions
Animals undergoing pretesting infusions of ifenprodil all received
vehicle infusions before training and drug infusions before STM
testing. All groups expressed high levels of freezing to the tone and
context during the STM test for tone and context conditioning (Fig.
3B). The ANOVAs for tone and context STM scores showed no significant effects (p > 0.05). Similarly,
relatively high levels of freezing were also seen in all groups after
infusion of ifenprodil or vehicle before testing of LTM for tone and
context. The ANOVAs were not significant (p > 0.05).
Histology
Cannula placements for rats in the intra-amygdala infusion
experiments are shown in Figure 4. Figure
4A shows the cannula placements for rats in the
second experiment that received intra-amygdala infusions of ifenprodil
followed by a test of LTM. Figure 4B shows the
cannula placements for rats in the third experiment that received ifenprodil followed by tests of STM and LTM. Cannula injector tips were observed throughout the rostrocaudal extent of the LA. Only
rats with cannula tips at or within the boundaries of LA were included
in the data analyses.
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Figure 4.
Cannula placements. A,
Cannula tip placements from rats infused with vehicle
(asterisks), 0.1 µg of ifenprodil
(circles), or 1.0 µg of ifenprodil
(squares) before training (black) or
before LTM testing only (gray). B,
Cannula tip placements from rats infused with vehicle
(asterisks), 0.1 µg of ifenprodil
(circles), or 1.0 µg of ifenprodil
(squares) before training (black) or
before STM and LTM testing (gray).
B, Basal nucleus; CE, central nucleus;
LA, lateral nucleus.
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DISCUSSION |
In present study, we examined the contribution of the NR2B subunit
of the NMDA receptor in the amygdala, especially the LA, to fear
conditioning. We determined whether selective blockade of this subunit
would interfere with the conditioning of fear to a tone and context
paired with footshock. We focused on the LA because it is the sensory
gateway into the amygdala, a site of plasticity, and the region in
which lesions or reversible functional inactivation prevents fear
conditioning from occurring (for review, see Davis, 1997; Fanselow and
LeDoux, 1999; Maren, 1999; LeDoux, 2000).
Effects of NR2B blockade on fear conditioning
Past studies that have examined the effects of NMDA blockade on
fear conditioning have mostly used the nonselective antagonist APV
(Campeau et al., 1992; Fanselow and Kim, 1994; Maren et al., 1996; Lee
and Kim, 1998). Consistent with a role in synaptic plasticity and
learning, these studies have found that intra-amygdala administration of APV impairs fear conditioning. However, because a number of studies
have also found that intra-amygdala infusion of APV disrupts fear
expression (Maren et al., 1996; Lee and Kim, 1998; Lee et al., 2001),
it is not possible to unambiguously conclude that the effects on
acquisition are caused by a disruption of plasticity in the amygdala.
Indeed, in LA and other amygdala regions, NMDA receptors have been
implicated in routine synaptic transmission (Li et al., 1995, 1996;
Maren, 1996; Weisskopf and LeDoux, 1999). This stands in contrast to
the hippocampus, in which the NMDA receptor plays little, if any, role
in synaptic transmission (Harris et al., 1984; Bashir et al., 1991;
Bliss and Collingridge, 1993; Malenka and Nicoll, 1999). NMDA receptors
have also been implicated in LTP in LA and B in some studies (Gean et
al., 1993; Huang and Kandel, 1998), although not in all (Chapman and
Bellavance, 1992; Watanabe et al., 1995; Li et al., 1998). Thus, it is
particularly important that studies examining the role of the amygdala
and NMDA receptors in learning and memory and synaptic plasticity control for effects on sensory processing and/or routine
transmission. The effect of ifenprodil on the induction and
expression of LTP in the LA is an important question that awaits
further study.
APV affects all aspects of NMDA channel function (Watkins and Olverman,
1987). Thus, we hypothesized that it might be possible to more easily
disrupt fear conditioning without affecting the expression of
previously conditioned fear by using an antagonist with partial and
selective effects on channel function. Unlike the NR1 subunit, which
has been primarily implicated in channel function, the NR2B subunit has
been implicated in regulation of channel function (Moyner et al., 1994)
and coincidence detection, which is likely to be an important cellular
event underlying fear conditioning. In fact, studies of transgenic mice
have shown that overexpression of the NR2B subunit throughout the
forebrain enhances learning and memory in several tasks, including fear
conditioning (Tang et al., 1999). We therefore examined the effects of
blockade of the NR2B subunit on fear conditioning by administering the selective antagonist ifenprodil either throughout the brain and body
(systemic injections) or directly in the amygdala. Systemic and
intra-amygdala injections of ifenprodil before conditioning significantly disrupted acquisition when tested within an hour of
training (STM) or 24 hr later (LTM), whereas injections either immediately before the STM test or 24 hr after training and immediately before the LTM test had no effect on the expression of fear
conditioning. The fact that both STM and LTM were disrupted in rats
that were given pretraining infusions suggests that the NR2B
subunit-mediated cellular events that strengthen synapses are initiated rapidly.
Although cannulas in our experiments were targeted for the LA, by
necessity drugs infused into LA will spread to nearby regions, especially the underlying basal nucleus and the nearby central nucleus
of the amygdala (CE). Thus, it is not possible from the present results
alone to say with certainty that the effects are attributable solely to an action in LA. However, selective infusions of
APV into the CE have been shown previously to be without effect on fear conditioning (Fanselow and Kim, 1994). Furthermore,
the fact that damage to LA but not the basal nucleus disrupts
auditory fear conditioning (Majidashad et al., 1996; Nader et al.,
2001) is consistent with the interpretation that infusions in this
region have their effects by way of an action in LA.
Although most previous studies using APV have found effects on both
acquisition and expression of fear conditioning (Maren et al., 1996;
Lee and Kim, 1998; Fendt, 2001; Lee et al., 2001), several studies have
found a selective effect on acquisition (Miserendino et al., 1990;
Gewirtz and Davis, 1997; Walker and Davis, 2000). These studies each
used the fear potentiated startle paradigm to measure fear
conditioning. This discrepancy could be attributable to the existence
of temporally distinct fear motor centers that mediate the different
fear conditioned responses (Lee and Kim, 1998). However, recent studies
using the same paradigm have found that both the acquisition and
expression of fear-potentiated startle are affected by APV (Fendt,
2001). Although it remains to be determined why APV sometimes has an
effect on fear expression and sometimes does not, it is possible that
ifenprodil offers a more reliable approach to studies of the role of
NMDA receptors in the amygdala and other brain regions in learning and memory.
Functional implications
Ifenprodil is a subtype-selective NMDA antagonist that antagonizes
the NMDA receptor either by causing a modal shift in the gating of the
ion pore (Legendre and Westbrook, 1991) or by stabilizing the
inactivated form of the ion channel (Reynolds and Miller, 1989).
Although both the NR2A and NR2B subunits are involved in channel gating
(Moyner et al., 1992), each subunit has different electrophysiological
and biochemical properties. The NR1-NR2B complex possesses slower
activation and deactivation and thus displays a longer rise and decay
time course as compared with the NR1-NR2A complex (Chen et al., 1999).
In vitro studies have shown that the NR1-NR2B complex
exhibits longer EPSPs than the NR1-NR2A complex (Moyner et al., 1994),
allowing a longer time window for coincidence detection in the former.
Given that coincidence detection is believed to be an important
function performed by NMDA receptors during learning (Tsien, 2000), the
NR2B subunit, which is highly prevalent in the brains of juveniles
(Sheng et al., 1994; Portera-Cailliau et al., 1996), may be
particularly important during plasticity and learning. Indeed, tyrosine
phosphorylation of NR2B has been linked with LTP in the hippocampus
(Rosenblum et al., 1996; Rostras et al., 1996), as well as to taste
learning in the insular cortex (Rosenblum et al., 1997).
One important question is whether or not the NR2B subunit constitutes a
major component of NMDA receptor function in the adult rat LA. To this
end, we have observed significant expression of the NR2B subunit in the
adult rat LA using a subunit-specific antibody (Rodrigues et al.,
2000). Moreover, recent studies have shown that the NR2B subunit
persists into adulthood, particularly in areas of the brain relevant to
cognitive tasks, such as the cortex and hippocampus (Jin et al., 1997;
Charton et al., 1999), as well as the thalamus and hypothalamus (Khan
et al., 2000). Thus, although NR2B expression does decline after
development (Sheng et al., 1994; Portera-Cailliau et al., 1996), it
appears that many NMDA receptors express the NR2B subunit well into
adulthood (Charton et al., 1999).
Because 1 hr may not be a sufficient time period to initiate gene
expression and protein synthesis, the STM results from the present
experiments suggest that the NMDA receptor recruits constitutively expressed molecules to fortify the synapse during the initial phases of
learning. The NR2B subunit is strongly associated with the enzyme
calcium-calmodulin kinase II (CaMKII) (Strack and Colbran, 1998), which
has been implicated in synaptic plasticity and memory, including fear
conditioning. Specifically, electrophysiological experiments have shown
that activation and autophosphorylation of  CaMKII after
Ca2+ influx via NMDA receptors is
essential for NMDA-dependent LTP in CA1 of the hippocampus
and spatial learning (Giese et al., 1998). In addition, regulated
expression of an CaMKII transgene in the LA and striatum results in
impaired fear learning (Mayford et al., 1996). Importantly, the
autophosphorylation-dependent targeting of CaMKII is specifically
linked to the NR2B subunit and not to the NR1 or NR2A
subunits (Strack and Colbran, 1998). Furthermore, the recruitment of
CaMKII into postsynaptic density structures, via association with
NR2B, may play a part in the rapid ultrastructural changes found in
synapses that undergo LTP (Buchs and Muller, 1996; Strack et al.,
2000).
NMDA receptor-mediated plasticity is also necessary for the long-term
changes that underlie fear conditioning. In our experiments, blockade
of NR2B receptors in the amygdala impaired not only STM, but also LTM
of contextual and tone fear. These findings are consistent with those
of other studies in the literature that have found NMDA
receptor-dependent changes in gene expression in the hippocampus after
induction of LTP or acquisition of hippocampal-dependent learning tasks
(Cammarota et al., 2000; Davis et al., 2000). Thus, Ca2+ entry through the NMDA receptor
appears to play an important role not only in the initial phases of
synaptic plasticity and learning, but also in later phases, possibly
because of activation of a variety of protein kinase signaling
cascades, such as PKA and MAPK, that are known to be essential for both
LTM formation of fear and synaptic plasticity in the amygdala (Huang et
al., 2000; Schafe and LeDoux, 2000; Schafe et al., 2000).
The present studies suggest that the NR2B subunit of the NMDA receptor
plays a distinct role in the plastic changes underlying fear
conditioning. Its key role in the acquisition but not the expression of
fear memories can perhaps be attributed to the unique electrophysiological and biochemical characteristics of this subunit. These findings have important implications for understanding the role
of the NMDA receptor complex in the processes of plasticity and
learning in general and open up new possibilities for studying the role
of the NMDA receptor in fear learning and synaptic plasticity in the
amygdala independently of its role in synaptic transmission.
| |
FOOTNOTES |
Received Jan. 26, 2001; revised June 11, 2001; accepted June 11, 2001.
This research was supported in part by National Institute of Mental
Health Grants R01 MH 46516, R37 MH 38774, and P50 MH 58911. This work
was also supported by a grant from the W. M. Keck Foundation to
New York University.
Correspondence should be addressed to Dr. Joseph E. LeDoux, Center for
Neural Science, New York University, 4 Washington Place, Room 809, New
York, NY 10003. E-mail: ledoux{at}cns.nyu.edu.
| |
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J. Pharmacol. Exp. Ther.,
December 1, 2003;
307(3):
1020 - 1029.
[Abstract]
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F. Zinebi, J. Xie, J. Liu, R. T. Russell, J. P. Gallagher, M. G. McKernan, and P. Shinnick-Gallagher
NMDA Currents and Receptor Protein Are Downregulated in the Amygdala during Maintenance of Fear Memory
J. Neurosci.,
November 12, 2003;
23(32):
10283 - 10291.
[Abstract]
[Full Text]
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M. Lopez de Armentia and P. Sah
Development and Subunit Composition of Synaptic NMDA Receptors in the Amygdala: NR2B Synapses in the Adult Central Amygdala
J. Neurosci.,
July 30, 2003;
23(17):
6876 - 6883.
[Abstract]
[Full Text]
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P. SAH, E. S. L. FABER, M. LOPEZ DE ARMENTIA, and J. POWER
The Amygdaloid Complex: Anatomy and Physiology
Physiol Rev,
July 1, 2003;
83(3):
803 - 834.
[Abstract]
[Full Text]
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A. Savonenko, T. Werka, E. Nikolaev, K. Zielinski, and L. Kaczmarek
Complex Effects of NMDA Receptor Antagonist APV in the Basolateral Amygdala on Acquisition of Two-Way Avoidance Reaction and Long-Term Fear Memory
Learn. Mem.,
July 1, 2003;
10(4):
293 - 303.
[Abstract]
[Full Text]
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C. Szinyei, O. Stork, and H.-C. Pape
Contribution of NR2B Subunits to Synaptic Transmission in Amygdaloid Interneurons
J. Neurosci.,
April 1, 2003;
23(7):
2549 - 2556.
[Abstract]
[Full Text]
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C. K. Cain, A. M. Blouin, and M. Barad
L-Type Voltage-Gated Calcium Channels Are Required for Extinction, But Not for Acquisition or Expression, of Conditional Fear in Mice
J. Neurosci.,
October 15, 2002;
22(20):
9113 - 9121.
[Abstract]
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J. W. Kinney, G. Starosta, A. Holmes, C. C. Wrenn, R. J. Yang, A. P. Harris, K. C. Long, and J. N. Crawley
Deficits in Trace Cued Fear Conditioning in Galanin-Treated Rats and Galanin-Overexpressing Transgenic Mice
Learn. Mem.,
July 1, 2002;
9(4):
178 - 190.
[Abstract]
[Full Text]
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S. M. Rodrigues, E. P. Bauer, C. R. Farb, G. E. Schafe, and J. E. LeDoux
The Group I Metabotropic Glutamate Receptor mGluR5 Is Required for Fear Memory Formation and Long-Term Potentiation in the Lateral Amygdala
J. Neurosci.,
June 15, 2002;
22(12):
5219 - 5229.
[Abstract]
[Full Text]
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E. P. Bauer, G. E. Schafe, and J. E. LeDoux
NMDA Receptors and L-Type Voltage-Gated Calcium Channels Contribute to Long-Term Potentiation and Different Components of Fear Memory Formation in the Lateral Amygdala
J. Neurosci.,
June 15, 2002;
22(12):
5239 - 5249.
[Abstract]
[Full Text]
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H. T. Blair, G. E. Schafe, E. P. Bauer, S. M. Rodrigues, and J. E. LeDoux
Synaptic Plasticity in the Lateral Amygdala: A Cellular Hypothesis of Fear Conditioning
Learn. Mem.,
September 1, 2001;
8(5):
229 - 242.
[Abstract]
[Full Text]
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TOP
ABSTRACT
INTRODUCTION
