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The Journal of Neuroscience, December 1, 1999, 19(23):10512-10519
L-Type Voltage-Gated Calcium Channels Mediate NMDA-Independent
Associative Long-Term Potentiation at Thalamic Input Synapses to the
Amygdala
Marc G.
Weisskopf,
Elizabeth P.
Bauer, and
Joseph E.
LeDoux
W. M. Keck Laboratory of Neurobiology, Center for Neural Science,
New York University, New York, New York 10003
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ABSTRACT |
Long-term potentiation (LTP) in the amygdala is a leading candidate
mechanism to explain fear conditioning, a prominent model of emotional
memory. LTP occurs in the pathway from the auditory thalamus to the
lateral amygdala, and during fear conditioning LTP-like changes
occur in the synapses of this pathway. Nevertheless, LTP has not been
investigated in the thalamoamygdala pathway using in
vitro recordings; hence little is known about the underlying mechanisms. We therefore examined thalamoamygdala LTP in
vitro using visualized whole-cell patch recording. LTP at these
synapses was dependent on postsynaptic calcium entry, similar to
synaptic plasticity in other regions of the brain. However, unlike many forms of synaptic plasticity, thalamoamygdala LTP was independent of
NMDA receptors, despite their presence at these synapses, and instead was dependent on L-type voltage-gated calcium channels. This was true when LTP was induced by pairing presynaptic activity with
either action potentials or constant depolarization in the postsynaptic
cell. In addition, the LTP was associative, in that it required
concurrent pre- and postsynaptic activity, and it was synapse specific.
Thus, although this LTP is different from that described at other
synapses in the brain, it is nonetheless well suited to mediate
classical fear conditioning.
Key words:
electrophysiology; in vitro; amygdala; LTP; calcium channels; fear; synapse
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INTRODUCTION |
Classical fear conditioning is a
robust form of learning that occurs throughout the animal kingdom. It
involves the pairing of an initially innocuous conditioned stimulus
(CS), such as a tone, with a noxious unconditioned stimulus (US), such
as an electric shock to the skin. After even a single pairing, the tone
will, when presented alone, elicit defensive and autonomic responses that are characteristically evoked by stimuli that cause harm or warn
of danger.
The neural pathways mediating fear conditioning involve the
transmission of sensory information about the CS to the amygdala and
the control of conditioned responses by output projections from the
amygdala (for review, see LeDoux, 1995 ). The CS enters the amygdala by
way of the lateral nucleus (LA) principally the dorsal subdivision
(LAd)which then distributes the inputs to other amygdala regions
(LeDoux, 1995; Pitkänen et al., 1997). Several lines of evidence
suggest that essential aspects of plasticity occur in this early stage
of processing within the amygdala (see Quirk et al., 1997).
Long-term potentiation (LTP) is a form of experience-dependent synaptic
plasticity that is believed to underlie learning (Milner et al., 1998)
and has been studied most extensively in the CA1 region of the
hippocampus. However relatively little progress has been made in
relating this synaptic plasticity to actual learning processes (Barnes,
1995; Eichenbaum, 1995; Stevens, 1998).
LTP has also been induced in several pathways involving the amygdala,
including pathways that transmit sensory inputs to the LA during fear
conditioning (Chapman et al., 1990; Clugnet and LeDoux, 1990; Chapman
and Bellavance, 1992; Rogan and LeDoux, 1995; Watanabe et al., 1995;
Brambilla et al., 1997; Huang and Kandel, 1998; Li et al., 1998).
Induction of LTP amplifies the processing of a CS-like acoustic
stimulus in the LA (Rogan and LeDoux, 1995), and fear conditioning and
LTP induction lead to similar changes in neural responses elicited by a
tone in the LA (Rogan et al., 1997). These observations, together with
the fact that the LA is required for conditioning (see above) and the
similarity between the stimulation protocols used in classical conditioning and those used to induce LTP (Brown et al., 1988), suggest
that a link between LTP and learning may be more easily established for
LA than hippocampal synapses (see Barnes, 1995; Eichenbaum, 1995;
Malenka and Nicoll, 1997; Stevens, 1998).
Studies examining amygdala LTP using in vitro preparations have
focused exclusively on the cortical inputs to the LA (Chapman et al.,
1990; Chapman and Bellavance, 1992; Gean et al., 1993; Watanabe et al.,
1995; Brambilla et al., 1997; Huang and Kandel, 1998; Li et al., 1998).
However, the in vivo studies linking amygdala LTP to fear
learning have involved the thalamic pathway (Rogan and LeDoux, 1995;
Rogan et al., 1997). Therefore, in an effort to uncover the synaptic
mechanisms that underlie fear learning via the thalamoamygdala pathway,
we examined the properties and mechanisms of LTP at these synapses
in vitro.
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MATERIALS AND METHODS |
Male Sprague Dawley rats (3-5 weeks old) were deeply
anesthetized with halothane, and the brain was rapidly removed and
transferred to ice-cold Ringer's solution. The Ringer's solution
contained (in mM): 115 NaCl, 3.3 KCl, 1 MgSO4, 2 CaCl2, 25.5 NaHCO3, 1.2 NaH2PO4, 5 lactic acid, and
25 glucose, equilibrated with 95% O2/5%
CO2. Picrotoxin (100 µM) was
included in all experiments to block fast GABAergic transmission.
Coronal slices (400 µm thick) containing the amygdala were cut, and
the cortex overlying the amygdala was cut away with a scalpel so that,
in the presence of picrotoxin, cortical epileptic burst discharges
would not invade the amygdala. The slices were placed in a holding
chamber at 32-34°C for 0.5 hr to improve subsequent patch success
and quality and then were allowed to return to room temperature for at
least another 0.5 hr before recording. Immediately before recording, a
slice was transferred to a superfusion recording chamber (Warner
Instruments) with a flow rate of 1.5-2.5 ml/min and held immobilized
beneath a nylon net stretched over platinum wire. All experiments were done at room temperature. An upright microscope equipped with infrared
differential interference contrast optics (Olympus Optical, Tokyo, Japan) was used to perform whole-cell patch recordings under
visual guidance. Recording electrodes were filled with (in mM): 130 K-gluconate, 0.6 EGTA, 2 MgCl2, 5 KCl, 10 HEPES, 2 Mg-ATP, 0.3 Na3-GTP, and, in some, 0.25-0.5% biocytin, pH
7.3 (290-300 mOsm). Membrane potentials were adjusted for a 10 mV
junction potential. The electrodes typically had resistances of 4-8
M .
Stimuli were delivered through bipolar stainless steel stimulating
electrodes (Frederick Haer) that were positioned while using a
low-power objective. This allowed easy identification of the LA,
triangular in shape in the coronal plane and bounded by the external
capsule laterally and the lateral association bundle medially. Thalamic
afferents travel rostrally toward the amygdala in the cerebral peduncle
and, at the level of the caudal amygdala, can be seen as a bundle
running parallel to the medial extent of the optic tract (LeDoux et
al., 1990). They then turn laterally, with some ramifying through the
striatum en route to the auditory cortex and with others coursing
through the ventralmost part of the striatum just above the central
nucleus of the amygdala, and terminate in LAd. By placing a stimulating
electrode in the ventral striatum, just medial to LAd, we activated
fibers that originate, at least in part, in the auditory thalamus (see
Fig. 1A). Stimulation intensities were kept low to
help avoid nonmonophasic components in the response, and they are
indicated for the responses shown in the figures. The stimulus duration
was always 150 µsec. Recordings were made using an AxoClamp 2B
amplifier (Axon Instruments). Signals were filtered at 3 kHz and
digitized at 5 kHz with a National Instruments analog-to-digital board.
Data were stored and analyzed using software written with LabVIEW
(National Instruments) running on an IBM-compatible personal computer.
All cells had membrane potentials more negative than  55 mV and action
potentials that exceeded 0 mV. Baseline responses were monitored at
0.05 Hz, and unless otherwise noted, cells were brought to 75 mV with
DC current to help avoid action potential generation by synaptic input.
Because LTP at synapses between the cells of area CA3 and CA1 of the
hippocampus cannot be induced after ~20 min of recording when using
whole-cell recording techniques (Manabe and Nicoll, 1994), in the
present experiments we attempted to induce LTP at input synapses to the amygdala within 15 min of entering whole-cell mode. In addition, because changes in response latency may reflect changes in
nonmonosynaptic responses, we excluded any experiment in which a
latency shift occurred after the LTP induction protocol. In all
experiments the series resistance was monitored throughout the
experiments, and if it changed by >15%, the data were discarded.
Values are expressed as means ± SEM unless SD is noted,
and potentiation is expressed as percent of baseline at the indicated time range after induction. All responses in one cell over the indicated time range were averaged to get one value per cell. These
were then averaged, and the indicated n refers to the number of cells. Significance was tested with a two-tailed, two-sample (except
where a paired test is indicated) Student's t test. All animals were handled in accordance with National Institutes of Health
and New York University guidelines. Drugs were applied by adding them
to the superfusing Ringer's solution. Drugs used were MK-801 and
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) from Research Biochemicals
(Natick, MA); D-2-amino-5-phosphonopentanoic acid
(D-APV) from Sigma (St. Louis, MO) and
Research Biochemicals; and
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid (BAPTA), nifedipine, and picrotoxin from Sigma. Drugs were made up in
stock solution and diluted 1000 times into the Ringer's solution.
Picrotoxin, MK-801, nifedipine, and CNQX stocks were made up in DMSO.
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RESULTS |
Recordings were made from LAd neurons, and a stimulating electrode
was placed just medial to the LA to activate thalamic afferents as they
course through the ventral striatum from near the optic tract to enter
the amygdala (Fig. 1A).
EPSPs in LA cells generated by this stimulation procedure increased in
amplitude as stimulation intensity increased (Fig.
1B). A late, presumably polysynaptic, component to
the response was also seen sometimes (Fig. 1B; see also, e.g., Fig. 4). Indeed, increasing divalent ion concentrations in
the extracellular bathing solution, which has been shown to suppress
polysynaptic responses (Jahr and Jessell, 1985; Sah and Nicoll, 1991),
was effective at suppressing later components of the response (Fig.
1C). In contrast, the early component of the EPSP persisted
in the presence of elevated divalent ions. Furthermore, in response to
changes in stimulus intensity the initial slope of the EPSP was graded,
and its onset latency did not change (Fig. 1B).
Together, these results suggest that the initial slope of the EPSP is
monosynaptic. Therefore, to eliminate di- or polysynaptic contamination
and analyze only monosynaptic input to the LA in the presence of normal
levels of divalents, we restricted our analysis to this portion of the
EPSPs.
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Figure 1.
Thalamic input to the LA. A,
Schematic of stimulating and recording electrode placement. Afferent
fibers from the thalamus enter the LA medially. All recordings were
made from cells in the dorsal subregion of the LA, which is the main
site of termination of fibers from the auditory thalamus (LeDoux et
al., 1990). CE, Central nucleus of the amygdala;
ec, external capsule; ic, internal
capsule; ot, optic tract. B, EPSPs
recorded in response to stimuli of increasing intensity (55, 70, 85, and 100 µA). The initial slope is graded with intensity. The action
potential contribution to the highest intensity example has been
truncated. C, EPSPs in another neuron (120 µA
intensity) in control conditions (2 mM
Ca2+, 1 mM Mg2+;
top) and after increasing the Ca2+
and Mg2+ concentrations to 12 mM each
(bottom). The nonmonosynaptic component is suppressed by
the increased divalent concentration. Traces are
averages of five responses.
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LTP induction
Although the exact cellular basis of fear conditioning is unclear,
presynaptic inputs to LA neurons from CS pathways presumably elicit
EPSPs that are somehow paired with postsynaptic action potentials
elicited by the US. We therefore used an LTP induction protocol that
involved pairing of pre- and postsynaptic activity: trains of
presynaptic stimulation were paired with depolarization of a
postsynaptic neuron in the LA. Specifically, LTP was induced by pairing
trains of 10 stimuli at 30 Hz with 1 nA, 5 msec depolarizations given
5-10 msec after the onset of each EPSP in the train. This pairing was
given 15 times at 10 sec intervals (for contrast with a second protocol
below we refer to this as "repeated pairing"). This has been shown
to be an effective stimulus for enhancing EPSPs between pairs of
neocortical neurons (Markram et al., 1997).
An example of a typical cell's response to the 30 Hz stimulation alone
is shown in Figure 2A,
and the response to the repeated-pairing protocol is shown in Figure
2B. Each depolarization given after each EPSP
in the train during the repeated-pairing protocol resulted in an action
potential (Fig. 2B). Repeated pairing resulted in an
increase in EPSP slope to 178 ± 20% of baseline (at 25-30 min; n = 7; see Materials and Methods) (Fig.
2C).
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Figure 2.
Repeated-pairing LTP of thalamoamygdala inputs.
A, Example of one cell's response to 10 stimuli (320 µA) delivered at 30 Hz is shown. B, The response of
the same cell when 1 nA, 5 msec depolarizations follow each EPSP in the
train (repeated pairing) is shown. Traces are averages
of 15 responses. C, Top, At time 0, this repeated
pairing (short solid bar) was given 15 times at 10 sec intervals. In control conditions
(filled circles) this induced LTP
(n = 7). Including 10 mM BAPTA in the
recording pipette (open circles)
prevented this LTP (n = 5). Bottom,
Traces before and 25 min after repeated pairing from
individual experiments in each case are shown and are averages of 10 responses (150 and 400 µA stimulation intensity for control and
BAPTA, respectively).
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Calcium-dependent LTP
Because calcium has been implicated in a variety of forms of
synaptic plasticity (Lynch et al., 1983; Zucker, 1989; Castillo et al.,
1994), we tested its involvement in LTP at thalamic inputs to the
amygdala by including the calcium chelator BAPTA in the recording
pipette solution. As can be seen in Figure 2C, the presence of BAPTA (10 mM) in the postsynaptic cell blocked
the induction of thalamic LTP (106 ± 5% at 25-30 min;
n = 5).
In the classic form of LTP seen in the CA1 region of hippocampus and
some other brain areas, calcium entry occurs through NMDA receptors
(Bliss and Collingridge, 1993; Malenka and Nicoll, 1993). Surprisingly,
NMDA receptor blockade with D-APV (50 µM) did
not affect thalamoamygdala LTP (control, 178 ± 20%;
n = 7; APV, 167 ± 12%; n = 9;
p = 0.62; at 25-30 min) (Fig.
3A, filled circles), even
though one-half this concentration of D-APV
effectively blocked the NMDA-mediated responses to 30 Hz stimulation
alone (Fig. 3B). To ensure NMDA independence further, we
performed another series of experiments in the presence of both the
competitive NMDA antagonist D-APV (50 µM) and the noncompetitive antagonist MK-801
(40 µM). Even this increased inhibition of the
NMDA receptor did not prevent the induction of LTP (182 ± 45%;
n = 6) (Fig. 3A, open diamonds). Thus,
thalamoamygdala LTP is independent of NMDA receptors in spite of a
contribution of NMDA receptors to baseline synaptic responses (Fig.
3B) (see also Weisskopf and LeDoux, 1999). Although calcium
entry into the postsynaptic cell is required for LTP induction, the
calcium does not seem to enter by way of NMDA receptors.
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Figure 3.
Repeated pairing-induced LTP is NMDA-independent,
VGCC-dependent LTP. A, Top, Repeated
pairing (short solid bar)
done at thalamic inputs in the presence of 50 µM
D-APV alone (filled circles;
n = 9) or with 40 µM MK-801
(open diamonds; n = 6) still results
in LTP (drugs applied as indicated by the long
solid bar, plus variable time before
breaking into the cell indicated by the dashed
bar). Bottom, Traces from
individual experiments before and 25 min after induction are shown (80 and 130 µA intensity for APV alone and with MK-801, respectively).
B, Example of an LA cell's response to 10 pulses (40 µA intensity) at 30 Hz at 66 mV in the presence of 10 µM CNQX and picrotoxin is shown. The subsequent block of
this response after addition of 25 µM D-APV
is superimposed. C, Top,
The L-type calcium channel blocker nifedipine (30 µM;
long solid bar, plus
variable time before breaking into the cell indicated by the
dashed bar) blocked the induction of LTP
at thalamic inputs (open circles; n = 8). Bottom, Nifedipine (30 µM;
long solid bar) did not
affect baseline synaptic transmission (filled
circles; n = 5) or the
depolarization induced by a 10 pulse, 30 Hz train (open
circles; n = 6; measured after the
fourth pulse). Inset, Traces from an
individual experiment before and 25 min after induction are shown (120 µA intensity). Traces are averages of 10 (A,
C) and 5 (B) responses.
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Significant postsynaptic calcium entry can occur through voltage-gated
calcium channels (VGCCs) (Miyakawa et al., 1992; Denk et al., 1996),
and the depolarization and action potentials evoked during repeated
pairing are likely to be effective in activating these channels.
Furthermore, other NMDA-independent forms of plasticity have been shown
to depend on L-type VGCCs (Kullmann et al., 1992; Huang and Malenka,
1993; Chen et al., 1998). Therefore, we tested whether blocking L-type
VGCCs with nifedipine affected thalamoamygdala LTP. In contrast to APV,
nifedipine blocked the induction of thalamoamygdala LTP (106 ± 11% at 25-30 min; n = 8) (Fig. 3C).
Nifedipine (30 µM) had no effect on baseline
transmission (Fig. 3C). In addition, to determine whether
nifedipine has any effects on transmission during the repeated-pairing
induction protocol, we tested for effects of nifedipine on a 10 pulse,
30 Hz train. The maximum depolarization caused by this stimulus usually
occurred after the fourth pulse in the stimulus, and monitoring the
level of this depolarization revealed that nifedipine had no effect
(103 ± 9% at 10-15 min; n = 6) (Fig.
3C). As an indicator of nifedipine's effects on the overall
depolarization induced by the train, we also calculated the integral
under the induced envelope of depolarization. This was not affected by
nifedipine either (105 ± 17% at 10-15 min; n = 6; data not shown). Thus, nifedipine does not, at this concentration,
prevent LTP via an inhibition of presynaptic transmitter release.
Alternate induction protocol
It is possible that the repeated-pairing protocol was so effective
at raising calcium levels that the need for calcium entry through NMDA
receptors was bypassed. Thus, a different induction protocol might
reveal an NMDA-dependent form of LTP. We therefore attempted to induce
LTP with a typical tetanic stimulation protocol (4 times 100 Hz for 1 sec, separated by 20 sec). However, this standard LTP protocol did not
induce LTP (103 ± 12% at 25-30 min; n = 6; data
not shown). Because depolarization played a role in the induction of
LTP with the repeated-pairing protocol, we subsequently gave tetanic
stimulation while injecting steady depolarizing current to bring the
membrane potential near to that at which action potentials were
triggered [63 ± 2 mV (SD); n = 6; compared
with 74 ± 5 mV (SD); above]. This protocol effectively induced
LTP (143 ± 12% at 25-30 min) (Fig.
4A, filled
circles).
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Figure 4.
Tetanus with depolarization induces
NMDA-independent, VGCC-dependent LTP. A,
Top, Tetanization, given while injecting DC current to
depolarize the cell near to the action potential discharge threshold
(Tet + Depol; arrow), induced LTP in
control conditions (filled
circles; n = 6) and in the presence
of 50 µM D-APV (open
circles; n = 6; APV applied as
indicated by the solid bar, plus variable
time before breaking into the cell indicated by the
dashed bar). Bottom,
Traces from individual experiments before and 25 min
after induction are shown (100 and 70 µA intensity for control and
APV, respectively). B, Top, Tetanization
with DC depolarization (Tet + Depol;
arrow) in the presence of both 50 µM
D-APV and 40 µM MK-801 still results in LTP
(filled diamonds;
n = 6). The L-type calcium channel blocker
nifedipine (30 µM) blocked the induction of this LTP at
thalamic inputs (open circles;
n = 7). In each case the drug was applied as
indicated by the solid bar, plus variable
time before breaking into the cell indicated by the
dashed bar. Bottom,
Traces from individual experiments (averages of 10 responses) for each case (60 and 40 µA stimulation intensity for
MK-801 and nifedipine, respectively) before and 25 min after induction
are shown.
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The NMDA dependence of this tetanically induced LTP was tested by
pairing the steady depolarization and the tetanus in the presence of 50 µM D-APV. As with the repeated-pairing
protocol described above, D-APV was ineffective at blocking
LTP induced by pairing tetanic stimulation with constant depolarization
[152 ± 11% at 25-30 min; n = 6; 62 ± 7 mV (SD) membrane potential during tetanus; p = 0.58 compared with control] (Fig. 4A, open circles). As
with repeated-pairing LTP, we further tested the NMDA dependence of
tetanus LTP by attempting to induce this LTP in the presence of
D-APV and MK-801. As with repeated-pairing LTP,
this increased inhibition of the NMDA receptor still did not block
tetanus induced LTP [145 ± 13% at 25-30 min; n = 6; 66 ± 3 mV (SD)] (Fig. 4B, filled
diamonds). Furthermore, nifedipine blocked this LTP [101 ± 8% at 25-30 min; n = 7; 63 ± 5 mV (SD) membrane potential during tetanus; p = 0.01 compared
with control] (Fig. 4B, open circles).
Tetanic stimulation has been shown to induce an NMDA-independent form
of LTP at excitatory synapses onto LA inhibitory cells (Mahanty and
Sah, 1998). This LTP was shown to be mediated by calcium entry through
calcium-permeable AMPA channels at synapses that lacked NMDA receptors.
To ensure that the present results were not being contaminated by such
LTP, all recorded cells were shown to have an NMDA response by
stimulating with trains of 10 stimuli at 30 Hz in the presence of CNQX.
The resulting responses were abolished by 25 µM
D-APV, indicating that we were not looking at LTP onto
inhibitory cells that lack NMDA receptors. This also verified
that the APV effectively blocked NMDA-mediated responses (see Fig.
3B).
Associative, synapse-specific induction mechanism
The trains of 10 stimuli at 30 Hz, as used in the repeated-pairing
protocol, when given without the paired depolarizations, were
insufficient to induce LTP (Fig.
5A), thus demonstrating the
necessity of the postsynaptic neuron to the LTP induction. In addition,
the depolarizing pulses given without the concomitant presynaptic
stimulation also failed to induce LTP (Fig. 5B), showing the
need for presynaptic input. A pre- and postsynaptic contribution to the
tetanus-induced LTP is also apparent because it was necessary to
depolarize the postsynaptic cell during the tetanus to elicit LTP
reliably. These results demonstrate an associative mechanism of LTP
induction in the amygdala, but one that does not rely on NMDA
receptors.
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Figure 5.
Associative, synapse-specific LTP at thalamic
input synapses to the LA. A, The 15 trains of 10 stimuli
at 30 Hz (short solid bar) without the
paired depolarizations did not induce LTP (open circles;
n = 5). B, The 15 trains of 1 nA, 5 msec depolarizations (short solid
bar) given without paired input stimulation also did not
induce LTP (open circles; n = 4).
C, LTP induced by repeated pairing (short
solid bar) at the thalamic pathway
(filled triangles) did not induce
LTP at a second, unpaired input (inverted
open triangles) onto the same cell
(n = 6). D, LTP induced by
tetanizing while depolarizing (Tet + Depol;
arrow) at the thalamic pathway
(filled triangles) did not induce
LTP at a second, untetanized input (inverted
open triangles) onto the same cell
(n = 6).
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In the CA1 region of the hippocampus, NMDA-dependent LTP is restricted
to the activated synapses in part because of the need for glutamate
release to activate postsynaptic NMDA receptors. Because LTP at
thalamic inputs to the amygdala is independent of NMDA receptors, we
tested whether synapse specificity still exists. In some of the LTP
experiments described above we placed a second stimulating electrode in
the external capsule dorsal to the LA to monitor simultaneously a
second input onto the recorded cell. This is the pathway most often
stimulated in past studies of amygdala LTP (see introductory remarks).
These corticoamygdala-elicited EPSPs did not change after LTP induction
in the thalamoamygdala pathway by either the repeated-pairing protocol
(thalamic, 179 ± 9%; n = 6; cortical, 111 ± 11%; at 25-30 min; p = 0.003, paired t
test) (Fig. 5C) or tetanic stimulation with depolarization
(thalamic, 151 ± 12%; n = 6; cortical, 98 ± 5%; at 20-25 min; p = 0.014, paired t
test) (Fig. 5D). This indicates that, in spite of the lack
of NMDA receptor involvement in thalamoamygdala LTP, the LTP is
nevertheless synapse specific.
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DISCUSSION |
During fear conditioning, auditory CS signals reach the LA via a
direct pathway from the auditory thalamus and indirectly by way of
projections from the auditory thalamus to the auditory cortex and from
there to the LA (LeDoux et al., 1990; Romanski and LeDoux, 1993).
Although the auditory thalamus was not included within the amygdala
brain slice, it was possible to stimulate regions in the slice through
which thalamic fibers traversed using past findings from tract-tracing
studies (LeDoux et al., 1990) to locate the trajectory. Thalamic fibers
en route to the LA course medially, entering the LA from the internal
capsule (see Fig. 1), and stimulating this site elicits physiological
responses that, in comparison with those elicited from external
capsuleor corticalstimulation, resemble thalamic inputs seen
in vivo, where the electrodes were actually placed in the
auditory thalamus and cortex (Li et al., 1995, 1996; Weisskopf and
LeDoux, 1999).
Distinct form of LTP
Given that LTP has been induced in thalamic CS pathways to the LA
in vivo (Clugnet and LeDoux, 1990; Rogan and LeDoux, 1995), that the best understood form of LTP in the hippocampus involves NMDA
receptors (Bliss and Collingridge, 1993; Malenka and Nicoll, 1993;
Huang et al., 1996; Milner et al., 1998), that NMDA receptors are
postsynaptic to the thalamic input (Li et al., 1995, 1996; Farb and
LeDoux, 1997; Weisskopf and LeDoux, 1999), and that NMDA receptor
blockade interferes with fear conditioning (Miserendino et al., 1990;
Maren et al., 1996; Gewirtz and Davis, 1997; Lee and Kim, 1998), a
natural question to ask is whether LTP in this pathways involves NMDA
receptors. Although past studies have found evidence both for (Huang
and Kandel, 1998) and against (Chapman and Bellavance, 1992; Watanabe
et al., 1995; Li et al., 1998) the involvement of NMDA receptors in LTP
of cortical input to the amygdala, LTP of the thalamic pathway has not
been studied in vitro previously. Thus no previous
information was available about its pharmacological basis. By pairing
trains of presynaptic input with trains of postsynaptic depolarizations
(repeated pairing) at thalamic input synapses, we found
NMDA-independent LTP.
The depolarizations used in the repeated-pairing protocol triggered
action potentials, which, in other cells, are known to result in
back-propagating action potentials (Stuart et al., 1997). These lead to
significant calcium entry into dendrites via VGCCs and even into
dendritic spines, particularly if paired with synaptic input (Miyakawa
et al., 1992; Denk et al., 1996). A similar sequence of cellular
events may be a component of the plasticity-inducing mechanism in LA
cells because we found that chelating calcium or blocking L-type VGCCs
prevented LTP.
It is interesting that LTP induced by repeated pairing is NMDA
independent, in spite of a contribution of NMDA receptors to transmission in this pathway, as seen both in vivo (Li et
al., 1995, 1996) and in vitro (present results) (Weisskopf
and LeDoux, 1999). One possibility is that the repeated-pairing
protocol we used was so effective at raising calcium levels via L-type
VGCCs that it obviated a need for calcium entry through NMDA receptors. Indeed, in the CA1 region of the hippocampus, where NMDA-dependent LTP
is the predominant form, synapse-specific potentiation that is
dependent on L-type VGCCs, but independent of NMDA receptors, can be
induced by pairing depolarizations with synaptic stimulation (Kullmann
et al., 1992; Chen et al., 1998). The same mechanism has been shown to
underlie other forms of NMDA-independent LTP as well (Grover and Tyler,
1990; Aniksztejn and Ben-Ari, 1991; Huang and Malenka, 1993).
Therefore, we attempted to induce LTP in the manner in which
traditional, NMDA-dependent LTP at the Schaffer collateral-CA1 synapse
is inducedwith 100 Hz tetanic stimulation.
Tetanic stimulation of thalamoamygdala inputs to the LA, unlike at
Schaffer collateral synapses in the hippocampus, did not induce LTP.
This may be attributable to the relatively hyperpolarized resting
membrane of LA cells compared with hippocampal pyramidal cells. That
this was the case is suggested by the fact that tetanic stimulation
given while depolarizing LA cells did induce LTP. Intriguingly,
however, this LTP was still NMDA independent and L-type VGCC dependent,
as with the repeated-pairing induction protocol. This pattern of
induction dependence is similar to that seen for a number of forms of
LTP in the hippocampus (Grover and Tyler, 1990; Aniksztejn and Ben-Ari,
1991; Kullmann et al., 1992; Huang and Malenka, 1993) and possibly CA3
(Kapur et al., 1998; but see Castillo et al., 1994). However,
thalamoamygdala LTP differs from both of these other forms of LTP:
mossy fiber-CA3 synapses have only a small NMDA component (Monaghan
and Cotman, 1985; Weisskopf and Nicoll, 1995); there is much evidence
that LTP at the mossy fiber synapse is entirely presynaptic (Staubli et
al., 1990; Zalutsky and Nicoll, 1990; Castillo et al., 1994; Weisskopf
and Nicoll, 1995); and in area CA1, L-type VGCC-dependent LTP is
induced only under conditions that bypass the primary, NMDA-dependent
LTP. In contrast, thalamoamygdala LTP is induced postsynaptically, but
the NMDA receptor is unnecessary. L-type VGCC-mediated LTP is clearly
the primary form at thalamoamygdala synapses and therefore may be
distinct even from VGCC-mediated LTP in CA1 at the molecular level.
Postsynaptic depolarization is a necessary component of thalamoamygdala
LTP induced by repeated pairing, but the concurrent presynaptic
stimulation is also a necessary component of the induction process,
implying that the LTP is associative. The induction conditions for the
tetanus-induced LTP are consistent with an associative mechanism as
well because LTP was not induced unless the tetanus was done while
depolarizing the postsynaptic cell. The LTP is also specific to the
stimulated pathway, presumably because of some consequence of the
presynaptic activation. In the case of NMDA-dependent hippocampal LTP
in the CA1 region, presynaptic activity is required to activate NMDA
receptors and achieve synapse specificity. This cannot be the role of
presynaptic activity at thalamic input synapses to the LA because the
LTP does not depend on NMDA receptors. Synapse specificity without NMDA
receptor involvement is also seen with LTP induced via L-type VGCCs in
area CA1 of the hippocampus, although the mechanism that provides the
synapse specificity has not been determined. At thalamoamygdala
synapses presynaptic activity could be necessary for calcium influx
through AMPA receptors (Hollmann et al., 1991). However, we found
linear I-V curves of thalamic input responses to the LA
(Weisskopf and LeDoux, 1999), suggesting that calcium-permeable AMPA
receptors do not play a significant role at these synapses (Hollmann et al., 1991). Another possibility, one that we favor, is that presynaptic activity helps achieve synapse specificity by activation of
metabotropic glutamate receptors, which have been implicated in LTP and
behaviorally mediated plasticity in other brain areas (Bashir et al.,
1993; Li et al., 1998).
Functional implications
The present results have a number of implications for the
mechanisms of fear conditioning. Although some studies suggest that NMDA blockade in the LA and adjacent areas interferes with the acquisition but not the expression of fear conditioning, others indicate that both acquisition and expression are interfered with (Miserendino et al., 1990; Maren et al., 1996; Gewirtz and Davis, 1997;
Lee and Kim, 1998). Given the role of NMDA receptors in synaptic
transmission in the LA (see Fig. 3B) (Li et al., 1995, 1996;
Danober and Pape, 1998; Weisskopf and LeDoux, 1999), this issue needs
to be carefully reconsidered to exclude the possibility that APV
disrupts fear learning by interfering with synaptic transmission. On
the other hand, if the plasticity underlying fear conditioning is in
fact NMDA dependent, then it is possible that fear conditioning involves NMDA-dependent LTP at intrinsic synapses within the LA or
other amygdala areas, but not at the thalamic input synapses.
Activation of calcium-dependent kinases has been implicated in fear
conditioning (Mayford et al., 1996), and our results clearly implicate
calcium in LTP at thalamic input synapses to the LA. Intriguingly,
although expression of activated calcium-calmodulin-dependent kinase
II (CaMKII) interfered with both amygdala- and hippocampal-dependent behavioral learning, it modified, but did not block, NMDA-dependent LTP
in area CA1 of the hippocampus (Mayford et al., 1996). Our results
indicate that calcium entry through VGCCs mediates LTP at thalamic
input synapses to the LA, which thus may be mechanistically different
from the NMDA-dependent form of plasticity found in the hippocampus. On
the other hand, it may be a form disrupted by the expression of
activated CaMKII, the manipulation that leads to the learning deficits
described above. Thus, it would be interesting to determine the
dependence of thalamoamygdala LTP on CaMKII.
It has been shown previously that fear conditioning and induction of
thalamoamygdala LTP lead to similar changes in field potentials
recorded in the LA (Rogan and LeDoux, 1995; Rogan et al., 1997) and
that after fear conditioning thalamic input synapses in the LA show
enhanced EPSPs (McKernan and Shinnick-Gallagher, 1997). The present
findings add to these previous results, showing that the induction
requirements for thalamoamygdala LTP are compatible with those proposed
for behavioral learning; it is specific to the activated pathway and
involves the co-occurrence of activity in the presynaptic CS input and
postsynaptic amygdala cell. These observations collectively suggest
that LTP occurs at thalamic input synapses in the LA during
conditioning. Whether this is a necessary and/or sufficient phenomenon
for behavioral learning remains to be determined.
| |
FOOTNOTES |
Received June 24, 1999; revised Sept. 8, 1999; accepted Sept. 16, 1999.
This work was supported by National Institutes of Health Grants
R01-MH46516 and K02-MH00956. M.G.W. is supported by National Institutes
of Health Grant F32-NS10222.
Correspondence should be addressed to Dr. Joseph E. LeDoux, New York
University, Center for Neural Science, 4 Washington Place, Room 809, New York, NY 10003. E-mail: ledoux{at}cns.nyu.edu.
| |
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S. M. Rodrigues, C. R. Farb, E. P. Bauer, J. E. LeDoux, and G. E. Schafe
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Physiol Rev,
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C.-H. Lin, C.-C. Lee, and P.-W. Gean
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A. Vyas, R. Mitra, B. S. Shankaranarayana Rao, and S. Chattarji
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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
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E. P. Bauer, G. E. Schafe, and J. E. LeDoux
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H. T. Blair, G. E. Schafe, E. P. Bauer, S. M. Rodrigues, and J. E. LeDoux
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W. Xu and D. Lipscombe
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M. Fendt
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G. E. Schafe, C. M. Atkins, M. W. Swank, E. P. Bauer, J. D. Sweatt, and J. E. LeDoux
Activation of ERK/MAP Kinase in the Amygdala Is Required for Memory Consolidation of Pavlovian Fear Conditioning
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Both Protein Kinase A and Mitogen-Activated Protein Kinase Are Required in the Amygdala for the Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation
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J. M. Schjott and M. R. Plummer
Sustained Activation of Hippocampal Lp-Type Voltage-Gated Calcium Channels by Tetanic Stimulation
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N. Ohkubo, N. Mitsuda, M. Tamatani, A. Yamaguchi, Y.-D. Lee, T. Ogihara, M. P. Vitek, and M. Tohyama
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G. E. Schafe and J. E. LeDoux
Memory Consolidation of Auditory Pavlovian Fear Conditioning Requires Protein Synthesis and Protein Kinase A in the Amygdala
J. Neurosci.,
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TOP
ABSTRACT
INTRODUCTION
