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Induction mechanisms for L-LTP at thalamic input synapses to the lateral amygdala: requirement of Ok kyung Lee, Chang-Joong Lee1 and Sukwoo ChoiCA 1Department of Neuroscience, Ewha Institute of Neuroscience (EIN), School of Medicine, Ewha Womans University, Jongno-Gu, Jongno-6-Ga, 70, Ewha Dong-Dae-Mun Hospital, Seoul 110 -783; 2Department of Biology, Inha University, Inchon 402-751, South Korea Received 4 February 2002; accepted 4 February 2002 L-LTP (late-phase long-term potentiation) at thalamo-amygdala sy- saturating concentrations before and during repeated tetanus. By napses is thought to be critical for auditory fear conditioning, but it contrast, the mGluR1antagonist CPCCOEt (80 mM) failed to show has not been clear what kinds of surface receptors and channels any e¡ects on L-LTP induction. Neither D-AP5 nor MPEP produced are involved in the induction phase of the L-LTP. Here we report any signi¢cant e¡ects on potentiated synaptic responses when that the NMDA receptor antagonist D-AP5 (50 mM), the L-type applied after L-LTP had been established. Thus, our data suggest calcium channel antagonist nifedipine (30 mM) and the metabotro- that NMDA receptors, L-type calcium channels and mGluR5 are pic glutamate receptor 5 antagonist MPEP (10 mM) prevented involved in L-LTP induction in the thalamo-amygdala pathway.
L-LTP induction when each antagonist was separately applied at c 2002 Lippincott Williams & Wilkins.
Key words: Amygdala; Brain slices; Fear conditioning; L-LTP; L-type calcium channel; NMDA receptor; Rat been explored up until recently. A study of E-LTP (early LTP is believed to be critical for learning and memory, and phase LTP) induced by pairing pre- and postsynaptic tremendous efforts have been made to find a link between activity reveals that the LTP induction is dependent on L- LTP and learning [1–3]. One of the best examples for the link type voltage-gated calcium channels, but not on NMDA between LTP and learning in the mammalian brain may be receptors [13]. In addition, an enduring form of LTP (L-LTP) cued conditioning, a form of fear conditioning that requires induced by multiple trains of high-frequency stimulation at the lateral amygdala. This form of fear conditioning is thalamic input synapses to the lateral amygdala has been produced by the pairing of a neutral tone as a conditioned shown to be dependent on protein synthesis, and is stimulus (CS) with a shock as an unconditioned stimulus mediated by protein kinase A and mitogen-activated (US). These two stimuli converge onto the lateral amygdala, protein kinase (see Fig. 7 in [14]).
and the coincidental presentation of the CS and US is Since L-LTP has an enduring phase, it may be more thought to induce fear conditioning by potentiating the relevant to study L-LTP as a cellular substrate for condi- synaptic strength of the CS pathway by a long-term tioned fear memory. Especially, receptors and channels potentiation-like mechanism [4,5]. The CS alone then could involved in induction mechanisms for L-LTP at thalamic produce a sufficient excitation of the lateral amygdala to input synapses to the lateral amygdala has not been clearly elicit conditioned fear. The CS comes into the lateral nucleus defined yet. Therefore, we have examined a possible role of of the amygdala via two routes: directly from the medial NMDA receptors, L-type calcium channels and group I geniculate nucleus and indirectly from the auditory cortex mGluRs in the induction of L-LTP at thalamic input [6,7]. Although the synapses of both of these projections undergo long-term potentiation, the in vivo and in vitrostudies linking amygdala LTP to fear learning have involvedthe thalamic pathway to the lateral amygdala [4,5]. How- ever, studies examining amygdala LTP using in vitro Brain slices were prepared using techniques described preparations have focused mainly on the cortical inputs to previously [15,16]. Sprague–Dawley rat (3–5 weeks old) were decapitated. The isolated whole brains were placed in Mechanisms for LTP (early phase or late phase LTP) in the an ice-cold (0–41C) modified artificial cerebrospinal fluid thalamic input synapses to the lateral amygdala have not (aCSF) solution. The composition of modified aCSF was as follows (in mM): 175 sucrose, 20 NaCl, 3.5 KCl, 1.25 Consistent with their results, the field potential in our NaH2PO4, 26 NaHCO3, 1.3 MgCl2, 11 D-(þ)-glucose. Coronal experimental condition had a constant and short latency of slices (400 mm) containing the amygdala were cut using a about 5 ms, followed high frequency (50 Hz) stimulation vibratome (Campden, UK), and were incubated in aCSF reliably and without failure, and it could be blocked by continuously bubbled at room temperature with 95% O2/ kynurenic acid (5 mM), a non-selective glutamate receptor 5% CO2 for  3 h before recordings. Just before transferring antagonist (data not shown, see also [14]). These findings the slice to the recording chamber, the cortex overlying the suggest that the field potential measured in the present amygdala was cut away with a scalpel so that, in the study reflects glutamatergic, monosynaptic responses at presence of picrotoxin, cortical epileptic burst discharges thalamic input synapses to the lateral amygdala. As shown in the previous studies, we also included picrotoxin in our The recording chamber was continuously superfused recording solution to block feedforward GABAergic inputs with aCSF (30–321C) at a flow rate of 1-2 ml/min. The aCSF to principal neurons in the lateral amygdala [17].
contained (in mM): 120 NaCl, 3.5 KCl, 1.25 NaH2PO4, 26 L-LTP at thalamic input synapses to the lateral amygdala NaHCO3, 1.3 MgCl2, 2 CaCl2, 11 D-(þ)-glucose. Picrotoxin has been shown to be induced by  3 trains of tetanus (10 mM) was included in all experiments to minimize fast (100 Hz, 1 s duration) [14]. Therefore, we have examined the GABAergic transmission [14]. The slices were incubated in effect of 3–5 trains of tetanic stimulation delivered at the recording chamber  30 min before the start of record- variable intervals to obtain maximal L-LTP. Five trains at 1 min intervals were found to be most effective for L-LTP To record field potentials at thalamic input synapses to induction. One successful example showed L-LTP lasting up the lateral amygdala, we placed a bipolar stimulating electrode in the thalamic afferent fibers innervating the In order to determine whether L-LTP induction at lateral amygdala, which is located in the ventral part of the thalamic input synapses to the lateral amygdala depends striatum, just above the central nucleus of the amygdala, just on NMDA receptors, L-type voltage-gated calcium channels medial to the lateral amygdala (see Fig. 7 in [14]). A trunk of or group I mGluRs, we applied antagonists for each the thalamic afferent fibers appeared to be well isolated candidate molecule before and during L-LTP induction.
from other structures and it could be easily visualized under Each antagonist was applied for a total of 20 min, 15 min our microscope. A stimulating electrode was located prior to repeated tetanus, and an additional 5 min during specifically on the trunk to elicit the field potential. The repeated tetanus. To enable a more reliable comparison, we recording electrode (41.0 MO) was filled with 0.9% NaCl obtained a pair of recordings for control and antagonist- and placed in the dorsal subregion of the lateral amygdala.
treated slices from the same animal. We first examined the Synaptic responses were elicited at 0.017 Hz. L-LTP was effect of the NMDA receptor antagonist D-AP5 (50 mM) on induced by five trains of tetanic stimulation (100 Hz, 1 s at induction of L-LTP in field potential recording experiments.
1 min intervals) with the same intensity and pulse duration D-AP5 prevented a potentiation of field potentials by five as the test stimuli. For the baseline field potential recording trains of tetanus. L-LTP could be induced in paired control 50% of the maximum amplitude was used. The range of slices (164 7 5.5% of control in the amplitude of field stimulus intensity and duration for each pulse is 0.1–0.3 mA potential at 2.5–3 h post-tetanus, n ¼ 6), but not in the presence of D-AP5 (Fig. 1a; 50 mM, 95 7 3.3% of control in Extracellular field potentials were amplified using a DP- the amplitude of field potentials 2.5–3 h post-tetanus, 301 amplifier (Warner Instrument Co., CT) and the output p o 0.0001, paired t-test, n ¼ 6). Exposure to D-AP5 com- was digitized with a DIGIDATA 1322A interface (Axon instruments Inc., Foster City, CA). The digitized signals In order to determine whether L-type voltage-gated were stored and analyzed with a PC computer using calcium channels are involved in the induction of L-LTP, pClamp 8 (Axon Instruments Inc., Foster City, CA).
we examined the effect of the L-type voltage-gated calcium Drugs used were D-AP5, nifedipine, picrotoxin and channel antagonist nifedipine (30 mM) on the induction of L- kynurenic acid from Sigma-Aldrich (St. Louis, MO). MPEP LTP. Five trains of tetanus resulted in the induction of L-LTP (2-methyl-6-(phenylethyl)-pyridine) and CPCCOEt (7-(hy- in paired control slices (169 7 5.8% of control in field droxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl es- potential amplitude 2.5–3 h post-tetanus). In contrast, pre- ter) were from Tocric Cookson (Ballwin, MO). Drugs were treatment of the L-type voltage-gated calcium channel made up in stock solutions and diluted more than 1000 antagonist nifedipine partially prevented the induction of times into aCSF. Picrotoxin, CPCCOEt and nifedipine were L-LTP (Fig. 1b; 122 7 4.6% of control in field potential amplitude at 2.5–3 h post-tetanus, p o 0.05 paired t-test,n ¼ 6). The potentiation in the presence of nifedipine wasmaintained for  3 h (p o 0.05, paired t-test), suggesting that NMDA receptors alone can support tetanus-induced L-LTP has been defined as a form of LTP that has an L-LTP. Neither nifedipine (30 mM) nor D-AP5 (50 mM) had enduring phase (4 3 h). In order to achieve a stable any effects on baseline synaptic responses in this pathway recording over 3 h we chose to measure the field potential evoked when the thalamic fibers onto the lateral amygdala An antagonist for NMDA receptors has been shown to were stimulated (see Materials and Methods). In the be effective in reducing conditioned fear when applied previous study [14], the field potential at thalamic input after conditioning [18]. This result raises the possibility synapses to the lateral amygdala has been characterized, and both the E-LTP and L-LTP were studied at this synapse.
mediated by NMDA receptors. Therefore, we examined INDUCTION MECHANISMS FOR L-LTP AT THALAMIC INPUT SYNAPSES Involvement of NMDA receptors and L-type voltage-gated calcium channels in the L-LTP induction. (a) L-LTP at thalamic input synapses onto the lateral amygdala was completely blocked by the NMDA receptor antagonist D-AP5 (50 mM, n ¼ 6; closed circles). (b) L-LTP at thalamic input synapsesonto the lateral amygdala was partially inhibited by the L-type voltage-gated calcium channel inhibitor nifedipine (30 mM, n ¼ 6; closed circles). Please notethat L-LTP was maintained even in the presence of nifedipine. (c) The potentiated synaptic responses during L-LTP were not altered by D-AP5 (50 mM,n ¼ 6).The averaged data traces taken before (left) and 3 h after (right) tetanus were shown at the top of the ¢gure. Calibration ¼ 3 ms, 0.2 mV.
the effect of an antagonist for NMDA receptors on the significant effects on baseline synaptic responses in this maintenance phase of L-LTP. We applied D-AP5 (50 mM) to the slices when L-LTP had been stably established (2–2.5 h post-tetanus). However, we failed to observe anysignificant effects of D-AP5 on the potentiated synapticresponses during L-LTP (Fig. 1c; 104.6 7 3.4% of control in the amplitude of field potentials, p 4 0.9, paired t-test, In the present study, we have found that L-LTP induction at n ¼ 4), suggesting that most of the potentiated synaptic thalamic input synapses onto the lateral amygdala is responses are mediated by non-NMDA receptors, most dependent on activation of NMDA receptors, L-type voltage-gated calcium channels and mGluR5. mGluR1 does Since D-AP5 (50 mM) completely blocked L-LTP induction, not appear to be involved in the induction of L-LTP.
activation of L-type calcium channels alone during repeated Compared to the previous studies of LTP in this pathway tetanus does not appear to support tetanus-induced L-LTP.
[13,14], our findings reveal unique characteristics of L-LTP; This would be either because calcium influx through L-type (1) tetanus-induced L-LTP at thalamo-amygdala synapses calcium channels during tetanus is too weak to induce L- depends upon activation of NMDA receptors, (2) L-type LTP or because calcium influx especially through NMDA calcium channel-dependent LTP has an enduring phase receptors during tetanus is required for the L-LTP induction.
(4 3 h). (3) L-LTP induction requires mGluR5 activation.
In order to determine whether enhanced activity of L-type LTP at thalamic input synapses to the lateral amygdala calcium channels helps to achieve L-LTP upon blockade of has been proposed as a cellular substrate for conditioned NMDA receptors, we examined L-LTP induction in the fear [4,5]. One approach to test the hypothesis would be to presence of BAY K 8644 (1 mM), a potentiator for L-type compare pharmacological and physiological characteristics calcium channels, as well as D-AP5 (50 mM), BAY K 8644 did of LTP and conditioned fear. NMDA receptors, L-type not have significant effects on baseline synaptic responses voltage-gated calcium channels and mGluR5, which have (Fig. 2a; n ¼ 3), whereas L-LTP could be induced. In the been shown to be involved in the induction phase of fear presence of 1 mM BAY K 8644 and 50 mM D-AP5 (Fig. 2b; conditioning [18–22], appear to mediate L-LTP induction.
155.0 7 4.7% of control in the amplitude of field potentials at Thus, L-LTP and conditioned fear share some of induction 2.5–3 h post-tetanus, p o 0.05, paired t-test, n ¼ 4). The mechanisms with each other, supporting the proposal that magnitude of the L-LTP with BAY K 8644 and D-AP5 was L-LTP is a cellular substrate for conditioned fear.
similar to that in paired control slices (p 4 0.3, paired t-test Perhaps the most critical finding in the present study is at 2.5–3 h post-tetanus, n ¼ 4; L-LTP in paired con- that mGluR5, but not mGluR1, is involved in the induction trol ¼ 171.0 7 6.0% of control in the amplitude of field of L-LTP. In the previous study [23], MPEP showed a potential at 2.5–3 h post-tetanus, p o 0.01, paired t-test, selective effect on mGluR5, but not on other glutamate n ¼ 4). One special feature of L-LTP induced in the presence receptors including NMDA receptors at the concentration of D-AP5 and BAY K 8644 was that the potentiation after used herein. No effects of the mGluR1 antagonist CPCCOEt repeated tetanus developed slowly over B1 h, implying that on L-LTP induction further suggest that MPEP selectively the early component of L-LTP depends upon activation of antagonized mGluR5, but not mGluR1, in our experiments.
NMDA receptors. Thus, our data suggest that L-LTP can be It is worthwhile to note that we observed the blocking effect achieved by enhanced calcium influx through L-type of 80 mM CPCCOEt on the induction of striatal LTD [24], calcium channels without intervention of NMDA receptor suggesting that 80 mM CPCCOEt is sufficient to block mGluR1 at least in case of striatal slices. Activation of Next we examined group I mGluRs (mGluR 1 and 5) on mGluR5 during L-LTP induction can stimulate PI hydrolysis L-LTP induction. We first tested the mGluR5 antagonist that leads to activation of PKC and increases in intracellular MPEP (10 mM) on induction of L-LTP. L-LTP could be calcium levels, which could contribute to the induction of induced in paired control slices (185 7 6.8% of control in the amplitude of field potential at 2.5–3 h post-tetanus, p o 0.05, Another interesting finding in this study is that L-LTP n ¼ 5), but not in the presence of MPEP (Fig. 3a; 10 mM, induction at thalamic input synapses to the lateral amygdala 113 7 5.4% of control in the amplitude of field potentials at depends upon both the NMDA receptors and L-type 2.5–3 h post-tetanus, p 4 0.3, paired t-test, n ¼ 5). Similar to voltage-gated calcium channels. The involvement of L-type the experiment using D-AP5, exposure to MPEP completely voltage-gated calcium channels in L-LTP induction would prevented L-LTP induction. We next examined the effect of be expected because of its involvement in the pairing- the mGluR1 antagonist CPCCOEt on L-LTP induction.
induced E-LTP induction shown in the previous study [13].
Although applied at a saturating concentration (80 mM), However, it is surprising to see the effect of an antagonist for CPCCOEt failed to block L-LTP induction (Fig. 3b; L-LTP NMDA receptors on the L-LTP induction since it did not in control ¼ 166 7 5.0%, n ¼ 5; L-LTP in CPCCOEt ¼ show any effects on the induction of E-LTP induced by 173 7 7.4%, n ¼ 5). We also examined the effect of MPEP pairing [13]. One possibility is that the repeated tetanic on L-LTP maintenance. We applied MPEP (10 mM) to the stimulation used herein produces a more localized depolar- slices when L-LTP had been stably established (2.5–3 h post- ization around the synapse, which would be sufficient for tetanus). MPEP failed to show any significant effects on the maximal activation of NMDA receptors. However, such a potentiated synaptic responses during L-LTP (Fig. 3c; local depolarization would allow at most a partial activation p 4 0.2, paired t-test, n ¼ 3), supporting the suggestion that of extrasynaptic L-type voltage-gated calcium channels.
mGluR5 is involved in the induction phase of L-LTP.
Thus, one can expect that NMDA receptors play a more Neither MPEP (10 mM) nor CPCCOEt (80 mM) had any important role in initiating calcium entry during the tetanus INDUCTION MECHANISMS FOR L-LTP AT THALAMIC INPUT SYNAPSES Restoration of L-LTP by exposure to BAY K 8644 in the presence of D-AP5. (a) BAY K 8644 (1 mM) alone did not alter baseline synaptic transmis- sion (n ¼ 3). (b) L-LTP was induced by repeated tetanus before and during exposure to 1 mM BAY K 8644 and 50 mM D-AP5 (n ¼ 4; closed circles). Pleasenote that the potentiation after repeated tetanus develops slowly. The averaged data traces taken before (left) and 3 h after (right) tetanus are shown atthe top of the ¢gure. Calibration ¼ 4 ms, 0.2 mV.
than L-type voltage-gated calcium channels do. By contrast, Restoration of L-LTP induction by BAY K 8644 upon it is possible that the massive postsynaptic depolarization blockade of NMDA receptors supports the idea that L-type used for the pairing-induced E-LTP in the previous study is calcium channels play a major role in the induction of so effective at raising calcium levels via L-type calcium NMDA receptor-independent LTP [13]. Furthermore, our channels that it obviates a need for calcium entry through data clearly indicate that L-type calcium channel-dependent LTP has an enduring phase in this pathway. Although an Involvement of mGluR5, but not mGluR1, in L-LTP induction. (a) L-LTP at thalamic input synapses onto the lateral amygdala was completely inhibited by the mGluR5 inhibitor MPEP (10 mM, n ¼ 5; open circles). (b) The mGluR1 antagonist CPCCOEt (80 mM, n ¼ 5; open circles) failed to block L-LTP induction at thalamic input synapses onto the lateral amygdala. (c) The potentiated synaptic responses during L-LTP were not altered by MPEP (10 mM,n ¼ 3).The averaged data traces taken before (left) and 3 h after (right) tetanus are shown at the top of the ¢gure. Calibration ¼ 5 ms, 0.2 mV.
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Acknowledgements: We thank Dr D.M. Lovinger for his comments on this manuscript.This research was supported by grants from the KMOST grant M1- 0108 - 00 - 0051 under the neurobiology research program to S.W.C.

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