| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Journal of Physiology (2002), 543.3, pp. 795-806
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.023424
 |
ABSTRACT |
|---|
 TopAbstract IntroductionMethodsResultsDiscussionReferences |
|---|
In the medial vestibular nuclei (MVN) of rat brainstem slices, the role of group II and III metabotropic glutamate receptors (mGluRs) and of the subtypes of group I mGluRs: mGluR1, mGluR5, was investigated in basal synaptic transmission and in the induction and maintenance of long-term potentiation (LTP). We used selective antagonists and agonists for mGluRs and we analysed the field potentials evoked by vestibular afferent stimulation before and after high-frequency stimulation (HFS) to induce LTP. The group II and III mGluR antagonist, (R,S)--2-methyl-4sulphonophenylglycine (MSPG), induced LTP per se and caused a reduction of the paired-pulse facilitation (PPF) ratio indicating an enhancement of glutamate release. This suggests that group II and III mGluRs are activated under basal conditions to limit glutamate release. Both the group II and III mGluR selective antagonists, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoate (LY341495) and (R,S)-
(Received 29 April 2002; accepted after revision 1 July 2002; first published online 19 July 2002)
Corresponding author S. Grassi: Dipartimento di Medicina Interna, Sezione di Fisiologia Umana, Università di Perugia, Via del Giochetto, Perugia I-06100, Italy. Email: isfisuma{at}unipg.it
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Metabotropic glutamate receptors (mGluRs) have various modulatory functions on neuronal excitability, transmitter release, and synaptic plasticity in the central nervous system (Pin & Duvoisin, 1995; Conn & Pin, 1997; Anwyl, 1999). To date, eight mGluR subtypes have been cloned which are subdivided into three groups based on their sequence homology, pharmacology and coupling to second messenger systems (Pin & Duvoisin, 1995; Conn & Pin, 1997). The group I mGluRs (mGluR1 and R5) couple to phospholipase C and inositol-1,2-5 triphosphate turnover, while group II (mGluR2 and R3) and group III (mGluR4, R6, R7 and R8) negatively couple to 3',5'-cyclic monophosphate turnover (Pin & Duvoisin, 1995; Conn & Pin, 1997). The role of mGluRs in synaptic transmission and plasticity depends on their coupling activity and their pre- and postsynaptic localization (Martin et al. 1992; Petralia et al. 1996; Shigemoto et al. 1996, 1997; Li et al. 1997): group II and group III mGluRs are presynaptic autoreceptors controlling glutamate release (Glaum & Miller, 1993; Burke & Hablitz, 1994; Gereau & Conn, 1995; Lovinger & McCool, 1995; Sànchez-Prieto et al. 1996; Schrader & Tasker, 1997; Anwyl, 1999; Bradley et al. 2000; Dubé & Marshall, 2000), while group I mGluRs play a role in regulating neuronal excitability and in facilitating the long-term potentiation and depression (LTP and LTD) at both pre- and postsynaptic level (Herrero et al. 1992; Sanchez-Prieto et al. 1996; Anwyl et al. 1999; Bortolotto et al. 1999; Manahan-Vaughan et al. 1999; Schwartz & Alford, 2000). Up to now these mechanisms are commonly accepted to explain the neuromodulatory events associated with activation of mGluRs. However, the threshold for activating these receptors and the sign of the effects may vary between different parts of the central nervous system (Anwyl, 1999), probably depending on the heterogeneity of synapses and the levels of physiological glutamate release.
It would therefore be worth investigating the role of mGluRs in the vestibular nuclei, since they are provided with different mGluR subtypes: group I mGluRs (mGluR1 and mGluR5), group II mGluRs (mGluR2, mGluR3) and group III mGluRs (mGluR7) (Shigemoto et al. 1992; Darlington & Smith, 1995; Ohishi et al. 1995; Neki et al. 1996; Romano et al. 1995; Puyal et al. 2000; Horii et al. 2001) and present a peculiar activity. Indeed, many vestibular neurons normally show high discharge, due to the input from primary vestibular afferents (Goldberg et al. 1985; Yagi & Ueno, 1988) and intrinsic pacemaker activity (Serafin et al. 1991; Johnston et al. 1994), and NMDA receptor dependent LTP can be induced by high-frequency stimulation (HFS) of vestibular afferents (Capocchi et al. 1992; Grassi et al. 1996; Grassi & Pettorossi, 2001).
The involvement of mGluRs in the vestibular synaptic transmission and plasticity of the medial vestibular nuclei (MVN) has been showed in our previous study, which hypothesized different roles for individual groups of mGluRs in this system (Grassi et al. 1998b). In fact, (R,S)--methyl-4-carboxyphenylglycine (MCPG), a broad spectrum mGluR antagonist, was able to provoke a potentiation per se, but it prevented the full development of this potentiation and reduced LTP, once induced (Grassi et al. 1998b). These results suggest, on the one hand, that mGluRs exert an inhibitory control on the basal glutamate release of vestibular neurons, so that their block enhances synaptic glutamate and induces LTP. On the other hand, they show a facilitatory role of mGluRs in the process leading to the full development of LTP. The predominance of inhibitory mGluRs over the facilitatory ones, under basal conditions, is also supported by the fact that an unspecific mGluR agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), reduced synaptic responses and prevented HFS-LTP (Grassi et al. 1998b). The mGluR subtypes involved in the basal inhibitory control of glutamatergic transmission have not been identified yet, even though group II and III mGluRs can be suggested. Conversely, group I mGluRs have been demonstrated to be responsible for the facilitatory effects (Grassi et al. 1999), and their activation seems to occur once vestibular potentiation is triggered causing its full expression and consolidation. In addition, it is likely that group I mGluRs are also involved at a presynaptic level in facilitating glutamate release during LTP development, and their activation requires a retrograde messenger, the platelet activating factor (PAF) (Grassi et al. 1998a, 1999, 2001).
This study was aimed at clarifying the role of different mGluR subtypes in controlling basal glutamate release and in facilitating synaptic plasticity in the MVN. In particular, we investigated the role of group II and III mGluRs and the possible specific action of mGluR1 and mGluR5, by using recently developed selective antagonists and agonists for these mGluRs. We demonstrated that group II and III mGluRs are involved in controlling glutamate release under basal conditions and found mGluR1 and mGluR5 to have opposite roles in the induction and development of vestibular LTP.
|
METHODS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Slice preparation
The experiments were performed on 122 brain stem slices prepared from 35 Wistar rats (150-250 g; Charles River, Como, Italy). The experiments were conducted in accordance with the guidelines of the institution's animal welfare committees (Bioethical Committee of the University of Perugia). Under ether anaesthesia, the animals were decapitated, and the cranium opened to expose the entire brain. The methods for preparing and maintaining the slices have been reported previously (Capocchi et al. 1992; Grassi et al. 1995). In brief, transverse 400 µm thick slices, containing the MVN, were incubated in warmed (30-31 °C) oxygenated artificial cerebrospinal fluid (ACSF), transferred after 1 h to an interface-type recording chamber and perfused at a rate of 2 ml min-1.
Electrophysiology
The field potentials elicited by vestibular afferent stimulation, were recorded in the ventral part (Vp) of the MVN, with 2 M sodium chloride filled micropipettes (resistance 3-10 M
) (Fig. 1). Since secondary vestibular neurons constitute a quite homogeneous population in this part of the MVN, the field potentials reflect the excitability of most of the neurons. In addition, we showed that there is a strict correspondence between field potential amplitude and extracellular unitary activity responses (Grassi et al. 1996). Therefore, we preferred the field potential analysis, rather than single cell recording, for making data collection and statistical evaluation easier. The recorded field potentials consisted of a large negative wave (N1), which follows the artefact and represents the monosynaptic activation of the secondary vestibular neurons (Fig. 1B and C). A second polysynaptic negative wave (N2), which is peculiar to field potentials evoked in the more dorsal part of the MVN, was rarely observed in our recording sites. As reported previously, (Grassi et al. 1996) the postsynaptic nature of the N1 wave was verified by a 3 ms interval paired-pulse test, which caused the disappearance of the N1 wave (Fig. 1C), and by using a Ca2+ -free solution (Fig. 1B). The recorded potentials were amplified, filtered with a wideband filter (0-10 kHz) and stored in a computer (Pentium PC) equipped with a data acquisition card (AT-MIO-16E-2, National Instruments, Austin, TX, USA).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 1. Recordings in the ventral part of the MVN A, recording sites in the ventral portion of the MVN (filled dots) and stimulating zone (black area) are plotted on the diagram of a brainstem slice. B, typical vestibular field potentials recorded in the ventral portion of MVN in normal and Ca2+-free solution. C, single pulse response is superimposed onto a 3 ms paired-pulse stimulation to show how N1 peak negative voltage was calculated compared to the baseline (vertical lines). Abbreviations: D, descending vestibular nucleus; Md, medial vestibular nucleus: dorsal portion; Mv, medial vestibular nucleus: ventral portion; L, lateral vestibular nucleus; S, superior vestibular nucleus; R, recording electrode; St, stimulating electrode. | ||
One bipolar NiCr-stimulating electrode was placed at the point where the vestibular afferents enter the MVN, which is in a narrow zone at the medial border of the lateral or descending vestibular nucleus (Fig. 1A). The distance between stimulating and recording electrodes was about 1 mm. We did not use more lateral positions, since, as previously reported (Grassi et al. 1999; Grassi & Pettorossi, 2000), the probability of eliciting field potentials was very low when the stimulating distance increased. However, our previous studies show no difference in the results between medial and lateral stimulation. In addition, in all our previous studies we were never able to evoke any measurable potential when the stimulating electrode was placed outside the loci where the vestibular afferents were probably localized and, in some cases, clearly visible. This was also confirmed by histological examination. This also rules out the possibility that the elicited responses are due to activation of fibres mediating internuclear interaction. Stimulus test parameters were: intensity 40-100 µA, duration 0.07 ms and frequency 0.06 Hz. We adjusted stimulus intensity so that the amplitude of N1 wave was 40-60 % of the maximum as determined by an input-output curve. HFS consisted of four bursts at 100 Hz applied with alternated polarity for 2 s with a 5 s interval. In all our previous studies we have shown that HFS induces LTP in the Vp of MVN in about 70 % of the cases, and has no effect in the remaining cases, while application of glutamate or related drugs induces LTP in all cases. In some slices, paired-pulse stimulation (interstimulus interval of 50 ms) was applied to evoke paired-pulse facilitation (PPF).
The recording and stimulating sites were marked, in each slice, by passing DC current of 50-100 µA for 10-20 s and subsequently verified by histological analysis. After fixation, slices were frozen, sectioned at 60 µm and stained for cells and fibres by Kluver-Barrera's method.
Materials
Drugs used were all purchased from Tocris Cookson (Bristol, UK) and included: the non-competitive mGluR1 antagonist, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt, 125 µM) (Litschig et al. 1999), the non-competitive mGluR5 antagonist, 2-methyl-6-phenylethynylpyridine (MPEP, 20 µM) (Gasparini et al. 1999), the selective mGluR5 agonist, (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 100 µM) (Doherty et al. 1997), the group I mGluR agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG, 100 µM) (Ito et al. 1992), the group II and III mGluR antagonist, (R,S)--2-methyl-4-sulphonophenylglycine (MSPG, 100 µM) (Jane et al. 1995), the competitive group II mGluR antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoate (LY341495, 200 nM) (Kingston et al. 1998), the group III mGluR antagonist, (RS)--methylserine-O-phosphate (MSOP, 100 µM) (Thomas et al. 1996), the group II mGluR agonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC, 100 µM) (Monn et al. 1996), the group III mGluR agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100 µM) (Tones et al. 1995) and the antagonist for NMDA receptors, D,L-2-amino-5-phosphonopentanoic acid (AP-5, 100 µM). The drug concentrations were chosen according to efficacious dose ranges reported in the above quoted literature.
Stock solutions of MPEP, DHPG, MSOP and AP-5 (10 mM) were dissolved in distilled water, while stock solutions of MSPG, CHPG, APDC, L-AP4 (10 mM) and LY341495 (100 µM) were dissolved in 0.1 N NaOH and that of CPCCOEt (5 mM) in 2 % dimethylsulphoxide (DMSO). As previously reported (Grassi et al. 1998a), DMSO at the final concentration (0.05 %), had no effect on baseline potentials and LTP induction. Working drug solutions were freshly prepared in ACSF and perfused at a rate of 2 ml min-1.
Data collection
We measured the amplitude of the N1 wave as the difference between the wave peak negative voltage and a baseline influenced by the electrical stimulus decay (Fig. 1C). To quantify this voltage decay, responses to 3 ms interval paired-pulse test were recorded before and after both drug and HFS application, since the second response of the paired-pulse stimulation represented only the electrical stimulus.
In the experiments in which PPF was tested, we calculated the PPF ratio by dividing the amplitude of the test (second) N1 wave by the conditioning (first) response. PPF is a short-term enhancement of a synaptic transmission used to detect possible changes in presynaptic function, since a decrease or increase in probability of neurotransmitter release is associated with an increase or decrease of PPF ratio, respectively (Hess et al. 1987; Manabe et al. 1993; Otmakhov, et al. 1993; Kleschevnikov et al. 1997).
To show the time course of the effects, the wave amplitudes were measured every 15 s and expressed as a percentage of the baseline (the mean of the responses recorded within the first 5 min of each experiment). PPF ratio was also expressed as a percentage of the control (the mean of PPF ratio calculated within the first 5 min of each experiment). To compare the effects within a single experiment and among different ones, we considered the average value and S.D. within a 5 min interval at the steady state of each experimental condition, for time course of the effects and at different times after induction of potentiation by drugs, for PPF. In each experiment the differences between the values were evaluated using analyses of variance (ANOVA) and Tukey's post hoc test. Statistical significance was established at P < 0.05.
|
RESULTS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Effect of blocking agents for group II and III mGluRs on the field potentials elicited in the Vp of MVN
We verified the effect of MSPG, a blocking agent for both group II and III mGluRs, which shows higher selectivity for presynaptic receptors (Jane et al. 1995), on the amplitude of the field potential N1 wave (n = 12). MSPG provoked a significant increase in the N1 wave in all the slices tested. This potentiation began 2-3 min after the start of drug infusion, it was completely established (131.05 ± 9.85 %, n = 12, Tukey's test; P < 0.01) within 10 min and persisted after drug washout throughout the recording period (> 60 min). HFS applied when this potentiation was completely established was not able to enhance it (Fig. 2A).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 2. Effect of the antagonist for group II and group III mGluRs on the field potential N1 wave In A, C and D the N1 wave amplitude was measured every 15 s, expressed as a percentage of the baseline and plotted as a function of time in single experiments (time course). In this and the following figures, the bars indicate the drug infusion period, and the arrow shows the HFS delivery time. A, time course of the MSPG effect. MSPG induces LTP which is not further enhanced by HFS. B, plot of mean percentage of the baseline PPF during potentiation induced by MSPG (n = 4). The first point represents the baseline PPF evaluated 5 min before the beginning of MSPG potentiation. Note the reduction of PPF ratio after LTP induction and its quick recovery to the control value. C, time course of the MSPG effect under AP-5 and after AP-5 washout. Note that, under AP-5, MSPG only provokes a transitory increase of the N1 wave. D, time course of the MSPG effect under CPCCOEt. | ||
To verify whether MSPG potentiation was due to an increase of glutamate release, we examined the PPF, a short-term enhancement of synaptic transmission used to detect changes in probability of neurotransmitter release (Hess et al. 1987; Manabe et al. 1993; Otmakhov et al. 1993; Kleschevnikov et al. 1997). During MSPG potentiation the PPF ratio decreased to 83.13 ± 5.17 % (n = 4), 5 min after the beginning of potentiation and quickly recovered to the control value at the drug washout (Fig. 2B).
MSPG-LTP was prevented by AP-5, since only a transitory increase of the N1 wave was observed during application of MSPG under AP-5 (112.56 ± 3.48 %, n = 3, Tukey's test; P < 0.05). LTP (136.83 ± 4.4 %, n = 3, Tukey's test; P < 0.01) could only be induced when MSPG was given after AP-5 washout (Fig. 2C). By contrast, MSPG potentiation was not affected by the block of mGluR1s, which are responsible for the full development of LTP induced by HFS (see below). In fact, in five out of six cases, MSPG under CPCCOEt, the selective antagonist for mGluR1, was still able to induce N1 potentiation (127.08 ± 8.93 %, n = 5). These effects can be considered to be full potentiations since the increases in the N1 wave were not significantly different compared to those induced by MSPG alone. This was also supported by the absence of the building up of potentiation, which was observed for the HFS-potentiation, at the CPCCOEt washout (see below) (Fig. 2D).
In order to define the individual contribution of group II and III mGluRs to the MSPG effect, we used the highly potent group II mGluR antagonist, LY341495 (Kingston et al. 1998) (n = 6) and the selective antagonist for group III mGluRs, MSOP (Thomas et al. 1996) (n = 6). LY341495 induced a long-lasting potentiation of the N1 wave in all the cases (131.12 ± 9.80 %, n = 6, Fig. 3A). By contrast, MSOP was only able to provoke N1 potentiation (132.70 ± 5.14 %, n = 3, Fig. 3B) in 50 % of the cases.
 |
View larger version [in this window] [in a new window] |
|
|
Figure 3. Effects of the selective antagonists and agonists for group II and group III mGluRs on the field potential N1 wave A and B, time course of the LY341495 and MSOP effects, respectively. The inserts show averaged field potentials (10 sweeps) before drug infusion (1) and after drug washout, when potentiation is established (2). Note that (1) and (2) correspond to numbers indicated on the plots. C and D, time course of the APDC and L-AP4 effects, respectively. Note that HFS applied during the drug depressant effect is not able to induce LTP. | ||
Effect of selective agonists for group II and III mGluRs on the field potentials and on the induction of the HFS-LTP in the MVN
We also tested the effect of the specific agonists for group II mGluRs (APDC, n = 6) and group III mGluRs (L-AP4, n = 6) on the amplitude of the N1 wave. Both the drugs provoked a significant reduction of the N1 wave (82.67 ± 4.14 %, n = 10, Tukey's test; P < 0.05) which began 2-3 min after the start of drug infusion but disappeared at the drug washout (Fig. 3C and D). However, APDC was able to induce this effect in all the cases examined, while L-AP4 was only efficacious in 66 % of the cases. HFS applied during the N1 depression induced by APDC (n = 3) and L-AP4 (n = 3), were never able to induce potentiation (Fig. 3C and D). This can be considered a specific inhibitory effect of the drugs as the normal failure percentage in inducing LTP by HFS is close to 30 % (see Methods).
Effect of the selective antagonist for mGluR1 on the induction and maintenance of HFS-LTP in the MVN
In all the slices tested (n = 13), bath application of the non-competitive antagonist for mGluR1, CPCCOEt (Litschig et al. 1999), had no effect on the amplitude of the field potentials under basal conditions, but it impeded the full development of LTP when HFS was delivered during administration of the drug. In fact, HFS under CPCCOEt induced potentiation of the N1 wave, which was significantly lower (121.01 ± 4.26 %, n = 9, Tukey's test; P < 0.05) compared with that induced by HFS alone (135.02 ± 4.80 %, n = 10) (Fig. 4A). At the drug washout potentiation could develop further on, to reach the level normally obtained after HFS (136.25 ± 4.24 %, n = 5), or decay within 25-30 min (n = 4) (Fig. 4A). Whether potentiation was fully expressed or abolished depended on the duration of drug application after HFS. A full potentiation was only observed when CPCCOEt washout began shortly after HFS (10 min), while potentiation faded away when the drug infusion lasted more then 15 min (Fig. 4A). In the remaining cases (n = 4), HFS under CPCCOEt failed to induce potentiation. These failures should not be attributable to the drug as they occur with the same frequency as that observed in normal slices (about 30 %, see Methods).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 4. Effect of the selective antagonist for mGluR1 on the induction and maintenance of HFS-long term potentiation A, time course of the effects of HFS under CPCCOEt infusion which lasted 10 min ( | ||
We also investigated the contribution of mGluR1 to the maintenance of N1 potentiation once induced by HFS. The infusion of CPCCOEt 10 min after HFS, when potentiation was established (135.90 ± 4.12 %, n = 5), caused a significant reduction of the N1 amplitude to 110.77 ± 2.93 % (n = 5, Tukey's test; P < 0.01). This effect was reversible as N1 wave regained its pre-infusion value after the drug washout (Fig. 4B).
Effect of the selective antagonist for mGluR5 on the induction and maintenance of HFS-LTP in the MVN
We analysed the effect of selective block of mGluR5 on the field potential N1 wave, by using MPEP, under basal conditions. This drug provoked a significant increase in the N1 wave in all the slices tested (n = 8). The N1 potentiation began 2-3 min after the start of drug infusion, it reached steady state (125.47 ± 6 %, n = 8, Tukey's test; P < 0.01) approximately 10 min later and persisted after drug washout throughout the recording time (> 60 min, Fig. 5A). Although MPEP potentiation was significantly lower, compared with that induced by HFS alone (135.02 ± 4.89 %, n = 10, Tukey's test; P < 0.05), HFS applied when potentiation was completely established did not enhance it (Fig. 5A).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 5. Effect of the selective antagonist for mGluR5 on the field potential N1 wave and on HFS-LTP A, time course of the MPEP effect. Potentiation induced by MPEP is not affected by HFS. B, effect of MPEP in the presence of CPCCOEt ( | ||
We tested the dependence of MPEP potentiation on NMDA receptor activation by using AP-5 (n = 5). In all the cases, under AP-5, MPEP was still able to induce potentiation (126.61 ± 3.33 %, n = 5), which was not different from that induced by MPEP alone (Fig. 5B). By contrast, MPEP potentiation was completely prevented by CPCCOEt (n = 4, Fig. 5B).
To verify whether MPEP potentiation was associated with an increase of glutamate release, we examined the PPF (n = 8). MPEP potentiation was always accompanied by a significant decrease in the PPF ratio. In all tested slices, the PPF ratio decreased to 74.84 ± 6.13 % (n = 4), 5 min after the beginning of potentiation and it gradually recovered to the control value, 30 min after potentiation induction (Fig. 5C). The values of PPF ratio were significantly different from the control at 5, 10, 15, 20 and 25 min after potentiation (Tukey's test; P < 0.05). We also tested (n = 4) whether the MPEP dependent reduction of the PPF ratio was still present under block of NMDA receptors. Under AP-5, the PPF ratio decreased to 72.54 ± 2.22 % (n = 4, Tukey's test; P < 0.05), 5 min after the beginning of potentiation and it showed a very similar time course to that observed when MPEP was used alone (Fig. 5C).
We also investigated the effect of mGluR5 block on potentiation induced by HFS. MPEP administered 10 min after HFS, when potentiation was completely established (134.14 ± 5.5 %, n = 5), had no effect in any of cases examined (Fig. 5D).
Effects of the agonists for group I mGluRs and mGluR5 on the field potentials in the MVN
As previously demonstrated (Grassi et al. 1999), activation of group I mGluRs by DHPG always induced a long-lasting potentiation of the N1 wave (132.03 ± 2.63 %, n = 6) which persisted after drug washout throughout the recording time, and it was not enhanced by HFS (Fig. 6A). DHPG potentiation was completely prevented by both AP-5 (n = 4, Fig. 6B) and CPCCOEt (n = 6, Fig. 6C). To obtain an intra-experimental control of this block, DHPG was applied to the same slices after drug washout and it induced N1 potentiation in all the cases (133.54 ± 3.49 %, n = 10, Fig. 6B and C).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 6. Effect of the agonist for group I mGluRs on the field potential N1 wave A, time course of the DHPG effect. DHPG induces LTP which is not further enhanced by HFS. B, time course of the effect of DHPG under AP-5 and after AP-5 washout. C, time course of the effect of DHPG under CPCCOEt and after CPCCOEt washout. Note that AP-5 and CPCCOEt fully block DHPG potentiation which is induced after AP-5 washout. | ||
We also tested the effect on the field potential N1 wave of CHPG, a recently described agonist showing high selectivity for mGluR5 (Doherty et al. 1997). CHPG had no effect on the amplitude of the N1 wave when applied to slices under basal conditions (n = 9). HFS delivered under CHPG in five cases was not able to induce N1 potentiation (n = 3) or even provoke a slight depression of the N1 wave (n = 2), which disappeared at the drug washout (Fig. 7A). In all these cases, HFS was able to induce LTP (133.67 ± 3.23 %, n = 5) after drug washout (Fig. 7A). In addition, CHPG had no effect on established HFS-potentiation (n = 3, not shown).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 7. Effect of the selective agonist for mGluR5 on the induction of potentiation by HFS and DHPG A, time course of the CHPG effect on the induction of potentiation by HFS. Note that under CHPG, HFS can induce a slight depression ( | ||
We examined the effect of mGluR5 activation on the capability of DHPG to induce potentiation, by using DHPG in the presence of CHPG (n = 7). In this condition, DHPG either had no effect (n = 4, Fig. 7B), or it provoked a potentiation of the N1 wave, which was significantly lower (126.35 ± 2.89 %, n = 3, Tukey's test; P < 0.05, Fig. 7C) compared to that induced by DHPG alone in this and in our previous study (Grassi et al. 1999). This potentiation could fade away or develop fully at the drug washout (Fig. 7C).
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Role of group II and III mGluRs in controlling synaptic transmission in the MVN
This study fully demonstrates our previous hypothesis (Grassi et al. 1998b) that group II and III mGluRs are tonically activated in the MVN, for modulating vestibular synaptic transmission under basal conditions. We observed that MSPG, a potent antagonist for group II and III mGluRs, induced LTP, and caused a reduction of the PPF ratio. This suggests that the block of group II and III mGluRs by MSPG is able to provoke an enhancement of glutamate release, under basal activity conditions, which is always sufficient for inducing LTP. This potentiation, like that induced by HFS (Capocchi et al. 1992; Grassi et al. 1996), depended on NMDA receptors, but, unlike HFS-potentiation (see below), the full development of MSPG potentiation was independent of mGluR1, since CPCCOEt, a selective blocking agent for mGluR1, did not prevent it. This difference can be tentatively explained by taking into account the possibility that during MSPG application the glutamate release may be high enough to make the mGluR1 synaptic facilitation unnecessary (or inactivated).
Regarding the separate role of group II and III mGluRs we found that both receptors inhibit vestibular synaptic transmission, but with a prevailing contribution of group II mGluRs. In fact, even though LTP was induced by the separate block of group II and III mGluRs, it was more frequently observed following application of a group II mGluR selective antagonist. Furthermore, the selective agonist for group II mGluRs reduced synaptic responses and blocked HFS-LTP with a higher probability compared to that for the selective group III mGluR agonist. The different contributions of the group II and III mGluRs may indicate a non-homogeneous expression of these receptors in the MVN or a different threshold of activation.
Role of mGluR1 and mGluR5 in the MVN
The group I mGluR subtypes, mGluR1 and mGluR5, do not have similar roles in the vestibular synaptic plasticity, in fact, their activation provokes opposite effects. While mGluR1 is necessary to facilitate HFS-LTP, mGluR5 prevents a facilitatory effect during the normal synaptic transmission. By using CPCCOEt, a selective antagonist for mGluR1 s, we demonstrated that these receptors are only activated during the development and consolidation of vestibular LTP. In fact, the mGluR1 block did not affect the field potentials under basal conditions, nor did it prevent the induction of potentiation by HFS. This finding is supported by a previous study in vivo, showing that the mGluR1 antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA) had no effect on behaviour when injected into the MVN (Gliddon et al. 2000). Conversely, CPCCOEt impeded the full expression of LTP that built up fully at drug washout, and it reduced potentiation, once induced. The involvement of mGluR1 in LTP consolidation is demonstrated by the fact that HFS-potentiation declined to nil when the interval between its induction and CPCCOEt washout was too long (more than 15 min). This effect supports the idea that mGluR1 is likely to be the key player in the facilitation of LTP consolidation mediated by group I mGluRs, since we previously observed similar decremental short-term effects when the activation of group I mGluRs was impeded long after HFS (Grassi et al. 1999). The full involvement of mGluR1 in the facilitatory effect of group I mGluRs on vestibular synaptic plasticity is also demonstrated by the fact that CPCCOEt completely prevented potentiation induced by DHPG, the selective agonist for group I mGluRs.
These results clearly show that, despite the coexistence of mGluR1 and mGluR5 in the MVN, all the functions we previously attributed to group I mGluRs, when using less selective mGluR antagonists (Grassi et al. 1998b, 1999), are mediated by mGluR1, which is the only receptor involved in facilitating synaptic plasticity, as mGluR5 has an inhibitory influence. In fact, the effects of the selective antagonist for mGluR5, MPEP, were just the opposite of those provoked by CPCCOEt. The finding of an inhibitory role of mGluR5 s is surprising, since these receptors are reported to mediate excitatory effects in many brain areas (Anwyl, 1999; Awad et al. 2000; Pisani et al. 2001). Furthermore, even though a growing body of literature suggests that mGluR1 and mGluR5 can have distinct physiological roles when present in the same neurons (Mannaioni et al. 2001), only in the substantia nigra has an opposite role of these receptors been recently demonstrated (Wittmann et al. 2001). In the MVN, we found that application of MPEP per se was always able to induce LTP, while it had no effect on HFS-potentiation, once induced. Conversely, CHPG, the specific mGluR5 agonist, prevented HFS-LTP without modifying the basal field potential amplitude. A possible explanation for these effects is that mGluR5 is already activated during normal synaptic transmission, to reduce the probability of inducing LTP, and becoming inactive when LTP is taking place. In addition, it is likely that mGluR5 exerts its effect by directly blocking mGluR1 activation, since MPEP potentiation was completely prevented by the mGluR1 antagonist, and DHPG potentiation was reduced by the mGluR5 agonist. Therefore, mGluR5 seems to be implicated in 'switching off' the facilitation of vestibular synaptic plasticity. But the mGluR5 inhibition on mGluR1 does not seem to be possible once mGluR1 is activated. In fact, while LTP could be reversed by blocking mGluR1, neither the block nor activation of mGluR5 were able to affect it. Overall, we suggest that, under the normal synaptic transmission, mGluR5 maintains mGluR1 in an inactivated state, but this balance between mGluR5 activation and mGluR1 inactivation changes, in some way, during intense synaptic activities, so that the full development and consolidation of LTP can take place.
Our previous results suggested that the mechanism by which activation of group I mGluRs facilitates LTP is mainly associated with a presynaptic increase of glutamate release, as shown by the reduction in the PPF ratio during DHPG potentiation (Grassi et al. 1999). The finding that MPEP potentiation is also associated with a decrease in the PPF ratio, suggests that the block of mGluR5 allows presynaptic mGluR1 to enhance glutamate release, so leading to LTP induction during basal synaptic transmission. It is interesting that, unlike LTP induced by HFS or by other drugs (Grassi et al. 1998, 1999; Grassi & Pettorossi, 2000), MPEP potentiation was independent of NMDA receptor activation. A tentative explanation for this discrepancy is that the inhibitory control of mGluR5 on mGluR1 is also exerted at a postsynaptic level. Therefore, when mGluR5 is blocked, postsynaptic mGluR1 becomes sensitive to glutamate, so that the intracellular Ca2+ concentration, required for LTP, can also be reached through mGluR activation alone, making the NMDA contribution irrelevant. This explanation is not in conflict with the dependence of DHPG potentiation on NMDA receptors. In fact, DHPG, which activates the facilitatory mGluR1, as well as the inhibitory mGluR5, may enhance glutamate release and postsynaptic sensitivity less than the selective mGluR5 antagonist. Therefore, in the case of DHPG, NMDA receptors which are activated easily compared to mGluR1s, may be indispensable for the full induction of LTP.
In conclusion, these results indicate that in the MVN the normal release of endogenous glutamate is able to activate presynaptic group II and III mGluRs, impeding unexpected enhancement of glutamate release. Conversely, in many brain regions, these receptors are only activated under specific conditions, such as during high-frequency synaptic transmission or when the clearance of glutamate is saturated or impaired (Anwyl, 1999; Dubé & Marshall, 2000). We suggest that a basal inhibitory control by mGluRs is present in neurons, such as those within the MVN, which normally show a powerful glutamatergic input and intrinsic pacemaker activity. In fact, a basal inhibition has also been found in the nucleus of the tractus solitarius (Glaum & Miller, 1993) and the hypothalamus (Schrader & Tasker, 1997), which, indeed, show glutamatergic high-frequency afferent inputs or burst activity neurons. Moreover, in the vestibular system, mGluR5 provides a further control of synaptic responsiveness, impeding the mGluR1 mechanism that facilitates LTP. This additional control seems to be useful since vestibular potentiation may vary in amplitude and duration in response to different levels of activation (Grassi et al. 2001). In fact, vestibular LTP is characterized by two steps (Grassi & Pettorossi, 2001), an early one, mediated by NMDA receptors leading to a partial and short-term potentiation, and a late one, mediated by mGluRs, which allows the enhancement and consolidation of potentiation, transforming it into a full LTP. Thus, the induction of both short- and long-lasting potentiation might be prevented by group II and III mGluRs, while the switch from one to the other type of potentiation might be controlled by mGluR5.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
| ANWYL, R. (1999). Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Research Reviews 29, 83-120 | [Medline] |
| AWAD, H., HUBERT, G. W., SMITH, J., LEVEY, A. I. & CONN, P. J. (2000). Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. Journal of Neuroscience 20, 7871-7879 | [Abstract/Full Text] |
| BORTOLOTTO, Z. A., FITZJOHN, S. M. & COLLINGRIDGE, G. L. (1999). Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus. Current Opinion in Neurobiology 9, 299-304 | [Medline] |
| BRADLEY, S. R., MARINO, M. J., WITTMANN, M., ROUSE, S. T., AWAD, H., LEVEY, A. L. & CONN, P. J. (2000). Activation of group II metabotropic glutamate receptors inhibits synaptic excitation of the substantia nigra pars reticulata. Journal of Neuroscience 20, 3085-3094 | [Abstract/Full Text] |
| BURKE, J. P. & HABLITZ, J. J. (1994). Presynaptic depression of synaptic transmission mediated by activation of metabotropic glutamate receptors in rat neocortex. Journal of Neuroscience 14, 5120-5130 | [Abstract] |
| CAPOCCHI, G., DELLA TORRE, G., GRASSI, S., PETTOROSSI, V. E. & ZAMPOLINI, M. (1992). NMDA-mediated long term modulation of electrically evoked field potentials in the rat medial vestibular nuclei. Experimental Brain Research 90, 546-550 | [Medline] |
| CONN, P. J. & PIN, J. P. (1997). Pharmacology and functions of metabotropic glutamate receptors. Annual Review of Pharmacology and Toxicology 37, 205-237 | [Abstract/Full Text] |
| DARLINGTON, C. L. & SMITH, P. F. (1995). Metabotropic glutamate receptors in the guinea pig medial vestibular nucleus in vitro. NeuroReport 6, 1799-1802 | [Medline] |
| DOHERTY, A. J., PALMER, M. J., HENLEY, J. M., COLLINGRIDGE, G. L. & JANE, D. E. (1997). (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu(5), but not mGlu(1), receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36, 265-267 | [Medline] |
| DUBÈ, G. R. & MARSHALL, K. C. (2000). Activity-dependent activation of presynaptic metabotropic glutamate receptors in locus coeruleus. Journal of Neurophysiology 83, 1141-1149 | [Abstract/Full Text] |
| GASPARINI, F., LINGENHÖHL, K., STOEHR, N., FLOR, P. J., HEINRICH, M., VRANESIC, I., BIOLLAZ, M., ALLGEIER, H., HECKENDORN, R., URWYLER, S., VARNEY, M. A., JOHNSON, E. C., HESS, S. D., RAO, S. P., SACAAN, A. I., SANTORI, E. M., VELIÇELEBI, G. & KUHN, R. (1999). 2-Methyl-6-phenylethynyl-pyridine (MPEP), a potent, selective, and systemically active mGlu5 receptor antagonist. Neuropharmacology 38, 1493-1503 | [Medline] |
| GEREAU, R. W. & CONN, P. J. (1995). Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in the hippocampal area CA1. Journal of Neuroscience 15, 6879-6889 | [Abstract] |
| GLAUM, S. & MILLER, R. (1993). Metabotropic glutamate receptors depress afferent excitatory transmission in the rat nucleus tractus solitarii. Journal of Neurophysiology 70, 2669-2672 | [Abstract] |
| GLIDDON, C. M., SANSOM, A. J., SMITH, P. F. & DARLINGTON, C. L. (2000). Effects of intra-vestibular nucleus injection of the group I metabotropic glutamate receptor antagonist AIDA on vestibular compensation in guinea pigs. Experimental Brain Research 134, 74-80 | [Medline] |
| GOLDBERG, J. M., BAIRD, R. A. & FERNANDEZ, C. (1985). Morphophysiological studies of the mammalian vestibular labyrinth. In Contemporary Sensory Neurobiology, ed. CORREIA, M. J. & PERACHIO, A. A., pp. 231-245. Alan R. Liss, New York | |
| GRASSI, S., DELLA TORRE, G., CAPOCCHI, G., ZAMPOLINI, M. & PETTOROSSI, V. E. (1995). The role of GABA in NMDA-dependent long term depression (LTD) of rat medial vestibular nuclei. Brain Research 699, 183-191 | [Medline] |
| GRASSI, S., FRANCESCANGELI, E., GORACCI, F. & PETTOROSSI, V. E. (1998a). Role of platelet-activating factor in long term potentiation of the rat medial vestibular nuclei. Journal of Neurophysiology 79, 3266-3271 | [Abstract/Full Text] |
| GRASSI, S., FRANCESCANGELI, E., GORACCI, F. & PETTOROSSI, V. E. (1999). Platelet activating factor and group I metabotropic glutamate receptors interact for full development and maintenance of long term potentiation in the rat medial vestibular nuclei. Neuroscience 94, 549-559 | [Medline] |
| GRASSI, S., FRONDAROLI, A., PESSIA, M. & PETTOROSSI, V. E. (2001). Exogenous glutamate induces short and long-term potentiation in the rat medial vestibular nuclei. NeuroReport 12, 2329-2334 | [Medline] |
| GRASSI, S., MALFAGIA, C. & PETTOROSSI, V. E. (1998b). Effects of metabotropic glutamate receptor block on the synaptic transmission and plasticity in the rat medial vestibular nuclei. Neuroscience 87, 159-169 | [Medline] |
| GRASSI, S. & PETTOROSSI, V. E. (2000). Role of nitric oxide in long-term potentiation of the rat medial vestibular nuclei. Neuroscience 101, 157-164 | |
| GRASSI, S. & PETTOROSSI, V. E. (2001). Synaptic plasticity in the medial vestibular nuclei: role of glutamate receptors and retrograde messengers in rat brainstem slices. Progress in Neurobiology 64, 527-553 | [Medline] |
| GRASSI, S., PETTOROSSI, V. E. & ZAMPOLINI, M. (1996). Low frequency stimulation cancels the high frequency-induced long lasting effects in the rat medial vestibular nuclei. Journal of Neuroscience 16, 3373-3380 | [Abstract/Full Text] |
| HERRERO, I., MIRAS-PORTUGAL, T. & SÀNCHEZ-PRIETO, J. (1992). Positive feedback of glutamate exocytosis by metabotropic presynaptic receptor stimulation. Nature 360, 163-166 | [Medline] |
| HESS, G., KHUNT, U. & VORONIN, L. L. (1987). Quantal analysis of paired pulse facilitation in guinea pig hippocampal slices. Neuroscience Letters 77, 189-192 | |
| HORII, A., SMITH, P. F. & DARLINGTON, C. L. (2001). Quantitative changes in gene expression of glutamate receptor subunits/subtypes in the vestibular nucleus, inferior olive and flocculus before and following unilateral labyrinthectomy in the rat: real-time quantitative PCR method. Experimental Brain Research 139, 188-200 | [Medline] |
| ITO, I., KOHDA, A., TANABE, S., HIROSE, E., HAYASHI, M., MITSUNAGA, S. & SUGIYAMA, H. (1992). 3,5-Dihydroxyphenylglycine: a potent agonist of metabotropic glutamate receptors. NeuroReport 3, 1013-1016 | [Medline] |
| JANE, D. E., PITTAWAY, K., SUNTER, D. C., THOMAS, N. K. & WATKINS, J. C. (1995). New phenylgly derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord. Neuropharmacology 34, 851-856 | [Medline] |
| JOHNSTON, A. R., MCLEOD, N. K. & DUTIA, M. B. (1994). Ionic conductances contributing to spike repolarization and after-potentials in rat medial vestibular nucleus neurones. Journal of Physiology 481, 61-77 | [Abstract] |
| KINGSTON, A. E., ORNSTEIN, P. L., WRIGHT, R. A., JOHNSON, B. G., MAYNE, N. G., BURNETT, J. P., BELAGAJE, R., WU, S. & SCHOEPP, D. D. (1998). LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37, 1-12 | [Medline] |
| KLESCHEVNIKOV, A. M., SOKOLOV, M. V., KUHNT, U., DAWE, G. S., STEPHENSON, J. D. & VORONIN, L. L. (1997). Changes in paired-pulse facilitation correlate with induction of long-term potentiation in area CA1 of rat hippocampal slices. Neuroscience 76, 829-843 | [Medline] |
| LI, H., OHISHI, H., KINOSHITA, A., SHIGEMOTO, R., NOMURA, S. & MIZUNO, N. (1997). Localization of a metabotropic glutamate receptor, mGluR7, in axon terminals of presumed nociceptive, primary afferent fibers in the superficial layers of the spinal dorsal horn: an electron microscope study in the rat. Neuroscience Letters 223, 153-156 | [Medline] |
| LITSCHIG, S., GASPARINI, F., RUEGG, D., STOEHR, N., FLOR, P. J., VRANESIC, I., PRÉZEAU, L., PIN, J. P., THOMSEN, C. & KUHN, R. (1999). CPCCOEt, a non-competitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Molecular Pharmacology 55, 453-461 | [Abstract/Full Text] |
| LOVINGER, D. M. & MCCOOL, B. A. (1995). Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGluR2 or 3. Journal of Neurophysiology 73, 1076-1083 | [Abstract] |
| MANABE, T., WYLLIE, D. J. A., PERKEL, D. J. & NICOLL, R. A. (1993). Modulation of synaptic transmission and long term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus. Journal of Neurophysiology 70, 1451-1461 | [Abstract] |
| MANAHAN-VAUGHAN, D., HERRERO, I., REYMANN, K. G. & SÀNCHEZ-PRIETO, J. (1999). Presynaptic group I metabotropic glutamate receptors may contribute to the expression of long-term potentiation in the hippocampal CA1 region. Neuroscience 94, 71-82 | [Medline] |
| MANNAIONI, G., MARINO, M. J., VALENTI, O., TRAYNELIS, S. F. & CONN, P. J. (2001). Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. Journal of Neuroscience 21, 5925-5934 | [Abstract/Full Text] |
| MARTIN, L. J., BLACKSTONE, C. D., HUGANIR, R. L. & PRICE, D. (1992). Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron 9, 259-270 | [Medline] |
| MONN, J. A., VALLI, M. J., JOHNSON, B. G., SALHOFF, C. R., WRIGHT, R. A., HOWE, T., BOND, A., LODGE, D., SPANGLE, L. A., PASCHAL, J. W., CAMPBELL, J. B., GRIFFEY, K., TIZZANO, J. P. & SCHOEPP, D. D. (1996). Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC): identification of a potent highly selective and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. Journal of Medical Chemistry 39, 2990-3000 | |
| NEKI, A., OHISHI, H., KANEKO, T., SHIGEMOTO, R., NAKANISHI, S. & MIZUNO, N. (1996). Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: an immunohistochemical study with a monoclonal antibody. Neuroscience Letters 202, 197-200 | [Medline] |
| OHISHI, H., AKAZAWA, C., SHIGEMOTO, R., NAKANISHI, S. & MIZUNO, N. (1995). Distributions of the mRNAs for L-2-amino-4-phospho-nobutyrate-sensitive metabotropic glutamate receptors, mGluR4 and mGluR7, in the rat brain. Journal of Comparative Neurology 360, 555-570 | [Medline] |
| OTMAKHOV, N., SHIRKE, A. M. & MALINOW, R. (1993). Measuring the impact of probabilistic transmission on neuronal output. Neuron 10, 1101-1111 | [Medline] |
| PETRALIA, R. S., WANO, Y. X., NIEDZIELSKI, A. S. & WENTHOLD, R. J. (1996). The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71, 949-976 | [Medline] |
| PIN, J. P. & DUVOISIN, R. (1995). The metabotropic glutamate receptors: structure and function. Neuropharmacology 34, 1-26 | [Medline] |
| PISANI, A., GUBELLINI, P., BONSI, P., CONQUET, F., PICCONI, D., CENTONZE, D., BERNARDI, G. & CALABRESI, P. (2001). Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-asparate responses in medium spiny striatal neurons. Neuroscience 106, 579-587 | [Medline] |
| PUYAL, J., SANS, N., VENTEO, S. & RAYMOND, J. (2000). Differential expression of metabotropic receptors during development in rat vestibular nuclei. European Journal of Neuroscience 12, suppl. 11, 341 | |
| ROMANO, C., SESMA, M. A., MCDONALD, C. T., O'MALLEY, K., VAN DEN POL, A. N. & OLNEY, J. (1995). Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. Journal of Comparative Neurology 355, 455-469 | [Medline] |
| SÀNCHEZ-PRIETO, J., BUDD, D. C., HERRERO, I., VÀZQUEZ, E. & NICHOLLS, D. G. (1996). Presynaptic receptors and the control of glutamate exocytosis. Trends in Neurosciences 19, 235-239 | [Medline] |
| SCHRADER, L. A. & TASKER, J. G. (1997). Presynaptic modulation by metabotropic glutamate receptors of excitatory and inhibitory synaptic inputs to hypothalamic magnocellular nucleus. Journal of Neurophysiology 77, 527-536 | [Abstract/Full Text] |
| SCHWARTZ, N. E. & ALFORD, S. (2000). Physiological activation of presynaptic metabotropic glutamate receptors increases intracellular calcium and glutamate release. Journal of Neurophysiology 84, 415-427 | [Abstract/Full Text] |
| SERAFIN, M., DEWAELE, C., KHATEB, A., VIDAL, P. P. & MÜHLETHALER, M. (1991). Medial vestibular nucleus in the guinea pig: I. Intrinsic membrane properties in brainstem slices. Experimental Brain Research 84, 417-425 | [Medline] |
| SHIGEMOTO, R., KINOSHITA, A., WADA, E., NOMURA, S., OHISHI, H., TAKADA, M., FLOR, P. J., NEKI, A., ABE, T., NAKANISHI, S. & MIZUNO, M. (1997). Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. Journal of Neuroscience 17, 7503-7522 | [Abstract/Full Text] |
| SHIGEMOTO, R., KULIK, A., ROBERTS, J. D., OHISHI, H., NUSSER, Z., KANEKO, T. & SOMOGYI, P. (1996). Target-cell specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381, 523-525 | [Medline] |
| SHIGEMOTO, R., SHIGETADA, N. & MIZUNO, M. (1992). Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in the adult and developing rat. Journal of Comparative Neurology 322, 121-135 | [Medline] |
| THOMAS, N. K., JANE, D. E., TSE, H. W. & WATKINS, J. C. (1996). -Methyl derivatives of serine-O-phosphate as novel, selective competitive metabotropic glutamate receptor antagonist. Neuropharmacology 35, 637-642 |
[Medline] |
| TONES, M. A., BENDALI, H., FLOR, P. J., KNOPFEL, T. & KUHN, R. (1995). The agonist selectively of a class III metabotropic glutamate receptor, human mGluR4a is determined by the N-terminal extracellular domain. NeuroReport 7, 117-120 | [Medline] |
| WITTMANN, M. M., HUBERT, G. W., SMITH, Y. & CONN, P. J. (2001). Activation of metabotropic glutamate receptor 1 inhibits glutamatergic transmission in the substantia nigra pars reticulata. Neuroscience 105, 881-889 | [Medline] |
| YAGI, T. & UENO, H. (1988). Behaviour of primary horizontal canal neurons in alert and anaesthetized guinea pigs. Experimental Neurology 101, 356-365 | [Medline] |
Acknowledgements
This research was supported by grant from the CNR and the MIUR. We wish to thank H. A. Giles (MA) for English language advice, and D. Bambagioni for technical assistance.
This article has been cited by other articles:
|
|
 |
|
  L. J. Volk, C. A. Daly, and K. M. Huber Differential Roles for Group 1 mGluR Subtypes in Induction and Expression of Chemically Induced Hippocampal Long-Term Depression J Neurophysiol, April 1, 2006; 95(4): 2427 - 2438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Roselli, M. Tirard, J. Lu, P. Hutzler, P. Lamberti, P. Livrea, M. Morabito, and O. F. X. Almeida Soluble {beta}-Amyloid1-40 Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses J. Neurosci., November 30, 2005; 25(48): 11061 - 11070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Grassi, C. Dieni, A. Frondaroli, and V. E. Pettorossi Influence of visual experience on developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei J. Physiol., November 1, 2004; 560(3): 767 - 777. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and 15 min (
) after HFS. Note that potentiation developed fully when CPCCOEt washout began 10 min after HFS, and it faded away when the drug infusion lasted more then 15 min. The insert shows averaged field potentials (10 sweeps) before HFS (1), after HFS under CPCCOEt (2) and after drug washout (3) in the case of short-term CPCCOEt infusion. B, time course of the effect of CPCCOEt applied after HFS, when potentiation is induced. The insert shows averaged field potentials (10 sweeps) after HFS (1), during CPCCOEt infusion (2) and after drug washout (3).
) or have no effect (