Group 1 metabotropic glutamate receptors contribute to slow-onset potentiation in the rat CA1 region in vivo

h’europhamcology, Vol. 36, No. 11112, pp. 1533-1538, 1997 0 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0028.3908/98 $19.00 + 0.00

Pergamon _ PII: SOOZS-3908(W)OOl56-1

Group 1 Metabotropic Glutamate Receptors Contribute to Slow--Onset Potentiation in the Rat CA1 Region in vivo and K. G. REXMANN

D. MANAHAN-VAUGHAN

Federal Institute for Neurobiology, Department of Neurophysiology, Brenneckestrasse D-39008 Magdeburg, Germany.

6, P.O. Box 1860,

(Accepted 8 August 1997)

Summary-It has been demonstrated in the CA1 region of the hippocampus in vitro, and in the dentate gyms and CA1 region in vivo, that application of the metabotropic glutamate receptor (mGluR) agonist, IS, 3R-amino cyclopentane 2,3-dicarboxylic acid triggers a slow-onset potentiation of synaptic transmission in the hippocampus. This study examined the involvement of group 1 and 2 mGluRs in this phenomenon in the CA1 region of freely moving rats. Drugs were applied via the lateral cerebral ventricle, and measurements were obtained from the CA1 region via permanently implanted electrodes. The group 1 mGluR agonists, 3,5dihydroxyphenylglycine (DHPG, 20-100 nmol/5 ,ul) and trans-azetidine-2,4-dicarboxylic acid (ADA, 100 nmol-1 pmol/S ~1) induced a dose-dependent potentiation of basal synaptic transmission. The mGluR antagonist R,S-a-:methyl-carboxyphenylglycine (MCPG, 1 ,umol), and the group1 mGluR antagonist, S-4carboxyphenylglycine (4CPG, 100 nmol) competely inhibited the effects of both DHPG and ADA. The group 2 mGluR agonist, (s)-4-carboxy-3-hydroxy phenylglycine (4C3H-PG, 50-200 nmoY5 ~1) induced a dosedependent decreasie of basal synaptic transmission. These results suggest that in the CA1 region in vivo, slowonset potentiation may be mediated by group 1 mGluRs. 0 1998 Elsevier Science Ltd. All rights reserved Keywords-Hippocampus, long-term potentiation (LTP), lS, 3R-ACPD, S4CPG, MCPG, ADA, 4C3HPG, slow-onset potenfation, mGluR receptor (group I), CAl.

The metabotropic glutamate receptor (mGluR) is believed to be a significant functional component of the mechanisms underlying synaptic plasticity, illustrated by the fact that mGluR activation plays an important role in the induction of both hippocampal long-term potentiation (LTP; Bashir et al., 1993; Behnisch and Reymann, 1993; Manahan-Vaughan and :Reymann, 1996) and long-term depression (LTD; Manahan-Vaughan, 1997; Huang et al., 1997). Pharmacological manipulation of mGluRs can also give rise to changes in synaptic efficacy. For example, activation of mGluRs via the selective mGluR agonist, lS, 3R-amino cyclopentane 2,3-dicarboxylic acid (ACPD), can give rise to depression or excitation of synaptic transmission and synaptic plasticity (Baskys and Malenka, 1991a,b; Bortolotto and Collingridge, 1993, 1995; Cahusac, 1994; Pook et al., 1992; Liu et al., 1993; McGuinness et al., 1991a,b; Aniksztejn et al., 1992; Behnisch and Reylmann, 1993; Mat&an-Vaughan and Reymann, 1995a). Furthermore, it has been demon*To whom correspondence should be addressed. Tel: 491391 62 63 409; Fax: 49/391 62 63 438; E-mail: manahan@ ifn-magdeburg.de.

strated that application of ACPD, both in vitro and in induces a slow-onset long-term potentiation of synaptic transmission in the rat hippocampus (Bortolotto and Collingridge, 1992, 1993, 1995; Manahan-Vaughan and Reymann, 1995a,b). Slow-onset potentiation in the hippocampal CA1 region is an intriguing form of synaptic plasticity, as it appears to depend solely on activation of mGluRs (Bortolotto and Collingridge, 1995). However, as yet little is known about the mGluR subtypes which contribute to this phenomenon. Three main subtypes of mGluRs are currently known. Group1 mGluRs are positively coupled to phospholipase C and activated by ACPD. Group 2 and 3 mGluRs are negatively coupled to cyclic AMP, and activated by ACPD and L-Zamino-4phosphonobutyric acid, respectively (Schoepp et al., 1992; Schoepp and Conn, 1993; Schoepp, 1994; Nakanishi, 1994). Previous work illustrated that pharmacological activation of group 3 mGluRs in vivo gives rise to depression of basal synaptic transmission and inhibition of LTP in the hippocampus (Manahan-Vaughan and Reymann, 1995~). This information, combined with the fact that ACPD preferentially activates group 1 and 2 vivo,

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mGluRs, excludes a role for group 3 mGluRs in slowonset potentiation. This study therefore set about to elucidate the involvement of group 1 and 2 mGluRs in slow-onset potentiation in the hippocampal CA1 region of freely moving rats. METHODS

Surgical preparation Male Wistar rats (7-S-weeks-old at the time of surgery) were anaesthetized with sodium pentobarbitone (“Nembutal”, 40 mg/kg, i.p.) and placed in a stereotactic unit. The skin above the skull was injected with the local anaesthetic, lidocaine (“Xylocaine”, Astra GmBH, Wedel, Germany), subsequent to the removal of an area of approximately 1 mm2 to expose bregma and the midline. The periosteum was then removed, and two stainless-steel screws (approx. 1 mm diameter) were inserted, without piercing the dura, into the skull over the left hemisphere via a drill hole. The screws were attached via silver wire to a socket connector. One served as a ground electrode (8 mm posterior to bregma; 4 mm lateral to the midline, coordinates according to Paxinos and Watson, 1986). The other was used as a reference electrode (4 mm anterior to bregma; 4 mm lateral to the midline). An outer guide cannula (approx. 0.5 mm internal diameter) was permanently implanted into the lateral cerebral ventricle of the right hemisphere (0.08 mm posterior to bregma; 1.6 mm lateral to the midline, and a depth of approx. 4 mm from the skull surface). Prior to the experiment the external cannula tip was sealed with latex so as to prevent leakage of the cerebrospinal fluid out of the ventricle. A Teflon-coated stainless-steel recording electrode (0.1 mm diameter) was placed in the stratum radiatum of the CA1 region of the right hemisphere (3.0 mm posterior to bregma; 2.8 mm lateral to the midline). A bipolar stimulating electrode (Teflon-coated stainless steel, 0.1 mm diameter wires) was placed in the Schaffer collaterals of the ipsilateral dorsal hippocampus (4.0 mm posterior to bregma; 3.8 mm lateral to the midline). The electrode wires were passed through a socket connector to enable recordings to be obtained. Recordings of evoked field potentials through the electrodes were obtained during electrode implantation to confirm their correct placement. The entire electrode assembly was then fixed to the skull using cyanoacrylate glue (Carl Roth GmBH, Karlsruhe, Germany), and built into a headstage using dental cement (Paladur, Heraeus Kulzer GmBH, Wehrheim, Germany). The animals were allowed between 7 and 10 days to recover from surgery. Following the conclusion of the study, histological verification of the localization of the electrodes and cannula was carried out. Throughout each experiment the animals could move freely, as the implanted electrodes were attached permanently to a socket which, in turn, was connected by a flexible cable to a stimulation unit and an amplifier during experiments. Evoked potentials were

displayed and analysed via a PC. Throughout the experiments the electroencephalograph of each animal was monitored continuously. Measurement of evoked potentials Field EPSPs were evoked in the stratum radiatum by stimulating at low frequency (0.025 Hz) with single biphasic square wave pulses of O.l-msec duration per half wave, generated by a constant current isolation unit. The field EPSP slope function was measured as the maximal slope through the five steepest points obtained on the first negative deflection of the potential. By means of input/ output curve determination the maximum field EPSP slope was found, and during experiments all potentials employed as baseline criteria were evoked at a stimulus intensity which produced 40% of this maximum. The latencies of the evoked field EPSPs were obtained by measuring the time to peak of the field EPSP from the preceding stimulus artifact. Compounds and drug treatment ACPD, DHPG, 4CPG, MCPG and (S)-4C3H-PG were obtained from To& Cookson Ltd., Bristol, U.K. ADA was obtained from Calbiochem, Germany. For injection, (,S)-4C3H-PG, 4CPG and MCPG were dissolved initially in 5 ~1 of a 1 mM NaOH solution, and then further mixed with 95 ~10.9% sodium chloride. DHPG and ADA were dissolved in 0.9% sodium chloride. The final injection volume applied to the animals was 5 ~1. The baseline field EPSP data were obtained by averaging the response to stimulating the Schaffer collaterals, to obtain five sweeps at 40-see intervals, every 15 min. Throughout the experiments, drug or vehicle injections were administered into the lateral cerebral ventricle following measurement of the baseline for 3&60 min, via an injection cannula which was inserted through the outer guide cannula. The injection cannula was inserted before the baseline measurements were taken, and left in place for the duration of the experiment so as not to create an artifact in recordings due to its insertion or removal. Where two injections took place the cannula was removed to permit the second injection, and then subsequently left in place for the duration of the experiment. The drugs were injected in a 5-~1 volume over a 6-min period via a Hamilton syringe and the effect of the compounds was monitored for 4 hr. Where an antagonist and agonist were applied during the same experiment, the baseline was monitored for 30 min followed by antagonist application, 30 min later agonist was applied, and the protocol followed as described above. In many of the cases the animals were used as their own controls, i.e. experiments using vehicle injection were carried out to confirm the stability of basal synaptic transmission in an individual animal, before a drug experiment occurred. The data were expressed as mean % pre-injection baseline reading f standard error of the mean (SEM). Statistical significance of the difference between means

Slow-onset potentiation

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Fig. 1. The effect of DI-IPG on basal synaptic transmission in the CA1 region. (A) DHF’G (100 nmol/S ~1) induces a slowonset potentiation of field EPSP in the CA1 region. Application of either MCPG (1 pmoY.5 ~1) or 4CPG (100 nmol) prior to DHPG (100 nmol) results in a complete inhibition of slowonset potentiation. (B) Original analog traces showing (i) field potentials evoked from the CA1 region before, 30 min and 4 hr following application of DHPG (100 nmoV5 ~1). **p < 0.01, ***, < 0.001.

was estimated using Student’s t-test. The probability levels interpreted as statistically significant were p
Effect of DHPG on basal synaptic transmission When DHPG was injected into the lateral cerebral ventricle as 20 nmol in a 5 ~1 volume, no effect on synaptic transmission was seen over a 4-hr period (n = 4, compared to controls n = 10). DHPG (50 nmol) induced a slight enhancement of field EPSP (n = 4), which was statistically significant’ from t = 45 min post-injection compared to controls (n = 12). When the concentration was then raised to 100 nlmol (n = 8), a clear enhancement of basal synaptic transmission was seen which was maintained until measurements ended at 4 hr postinjection (Fig. 1). At t ==30 min post-injection the field EPSP slope function was 121 f 6% compared to 95 f 3% in controls (n = 12, p < 0.05). At t = 4 hr postinjection, field EPSP was 149 f 14% in drug injected rats and 97 f 3% in controls (p ~0.001). The mGluR antagonist MCPG (1 pmol/S ~1, n = 7) completely inhibited slow-onset potentiation induced by DHPG (100 nmol, p < 0.01 from t = 30 min post-DHPG injection, Fig. 1). This concentration of MCPG has no

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Fig. 2. The effect of ADA on basal synaptic transmission in the CA1 region. (A) ADA (1 pmol/S ~1) induces a slow-onset potentiation of field EPSP in the CA1 region. Application of either MCPG (1 pmoV5 ~1) or 4CPG (100 nmol) prior to ADA (1 pmol) results in a complete inhibition of slow-onset potentiation. (B) Original analog traces showing field potentials evoked from the CA1 region before, 30 min and 4 hr following application of ADA (1 pmol/5 ~1). *p < 0.05, ***p < 0.001.

independent effects on basal synaptic transmission in the CA1 region (Mar&ran-Vaughan and Reymann, 1995b). Similarly, the group 1 mGluR antagonist, 4CPG (100 nmol/S ~1, n = 5) completely inhibited the slowonset potentiation induced by DHPG (100 nmol, p < 0.05 from t = 30 min post-DHPG injection, Fig. 1). It was shown previously that 4CPG has no independent effects on CA1 basal synaptic transmission (Mar&ran-Vaughan, 1997). No alteration in EEG was seen during the duration of the experiments.

Effect of ADA on basal synaptic transmission ADA (100 nmol in 5 ~1) had no effect on synaptic transmission over a 4-hr period (n = 8, compared to controls n = 12). Similarly, no significant effect on baseline was seen with 500 nmol ADA (n = 4). When ADA was applied at a concentration of 1 pmol (n = 6) an enhancement of basal synaptic transmission was seen however, which was maintained until measurements ended at 4 hr post-injection (Fig. 2(A, B)). At t = 30 min post-injection the field EPSP slope function was 111 f 5% compared to 101 f 4% in controls (p x0.05). At t = 4 hr post-injection, field EPSP was 152 f 9% in drug injected rats and 104 f 3% in controls. Both MCPG (1 pmol/S ~1, p c 0.05 from t = 75 min post-ADA injection, n = 6) and 4CPG (100 nmol/S ,ul, p < 0.05 from t = 30 min post-ADA

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Fig. 3. The effect of 4C3H-PG on basal synaptic transmission in the CA1 region. (A) 4C3H-PG (100 rmroY5 ~1) and vehicle injection produce no effect on basal synaptic transmission over a 4 hr recording period. However, 4C3H-PG in a concentration 200 nmol/5 ,LJinduces a depression of field EPSP in the CA1 region. (B) Original analog traces showing the field potentials evoked from the CA1 region before, 75 mm and 4 hr following application of 4C3H-PG (200 nmol/5 ~1). *p c 0.05.

IZ= 5) completely inhibited the slow-onset potentiation induced by ADA (1 pmol, Fig. 2). No alteration in EEG was seen during the duration of the experiments.

injection,

Effect of (S)-4C3H-PG on basal synaptic transmission When (S)-4C3H-PG was injected into the lateral cerebral ventricle as 50 run01 (n = 4) or 100 nmol (n = 4) in a 5 ,~l volume, and the baseline response monitored for four subsequent hours, no effect on synaptic transmission was seen (compared to vehicleinjected controls, n = 12). When the concentration applied was raised to 200 nmol a significant decrease in baseline was obtained (Fig. 3(A, B)). At t = 75 min postinjection a baseline decrease to 86 f 7% was seen which was significant from control values 102 * 3% (p < 0.05). This decrease was maintained as far as the end of the recording period, at 4 hr, and at this time point the decrease was 81 f 10% compared with 103 f 3% in controls 0) < 0.05). No alteration in EEG was seen during the duration of the experiments. DISCUSSION The findings of this study show that slow-onset potentiation in the hippocampal CA1 region can be stimulated through application of mGluR group 1 agonists but not via activation of group 2 mGluRs. DHPG (Ito et aZ., 1992; Schoepp et al., 1994; Gereau and Conn, 1995) and ADA (Kozikowski et al., 1990; Favaron et al., 1993; Manahan-Vaughan et al., 1996) are both specific group 1 mGluR agonists which increase phosphoinositide hydrolysis in hippocampus. Both ago-

and K. G. Reymann nists convert short-term potentiation (STP) into robust LTP when applied either before or after STP induction has taken place (Mar&an-Vaughan and Reymann, 1996). In this study, application of DHPG produced a dose-dependent slow-onset potentiation which was very similar in profile to the previously reported response induced by ACPD (Manahan-Vaughan and Reymann, 1995b). This supports the possibility that group 1 mGluRs play an important role in the induction of slow-onset potentiation in vivo. Furthermore, this finding is consistent with the involvement of post-synaptic Ca2+dependent modifications within CA1 neurones in the induction of slow-onset potentiation, as postulated by Bortolotto and Collingridge (1995). Group 1 mGluRs are predominantly localized postsynaptically (Lujan et al., 1996). Activation of these mGluR subtypes gives rise to stimulation of phospholipase C (PLC) which, in turn, results in the production of diacylglycerol (which stimulates protein kinase C) and inositol trisphosphate (B’s). IPs can act at IP3 receptors on intracellular calcium stores and result in Ca2+-release inside the post-synaptic neuron (Pin and Duvoisin, 1995 for review). Activation of Ca2+-dependent processes may underlie the increase in a-amino-3-hydroxy-5-methyl-4isoxazoleproprionate (AMPA) receptor-mediated conductances which are a component of ACPD-induced slow-onset potentiation in the CA1 region (Bortolotto and Collingridge, 1995). ACPD is an agonist at both group 1 and 2 mGluRs (Pin and Duvoisin, 1995). It has been reported that ADA, aside from group 1 mGluR effects, can act at human group 2 mGluRs (Knopfel et al., 1995), although in our hands this effect was not seen in rat tissue (ManahanVaughan et al., 1996). However, it may be the case that ACPD and ADA induce slow-onset potentiation via the interaction of subtypes of more than one mGluR group. Group 1, 2 and 3 mGluRs are localized in the hippocampal CA1 region (Roman0 et al., 1995; Saugstad et al., 1994; Fotuhi et al., 1994; Shigemoto et al., 1992). It is not likely that group 3 mGluRs mediate slow-onset potentiation, however, as it has been shown previously in vivo that application of the group 3 mGluR agonist L-2amino phosphonobutyrate can negatively modulate basal synaptic transmission and long-term potentiation in CA1 (Manahan-Vaughan and Reymaim, 1995~). However, an interaction between group 2 and group 1 mGluRs in induction of slow-onset potentiation cannot be excluded. To examine whether group 2 mGluRs contribute to slow-onset potentiation, the agonist (S)-4C3H-PG was applied. (S)-4C3H-PG produced a decrease in basal synaptic transmission, however, which is in agreement with other reports (Davis and Laroche, 1996). This finding indicates that activation of group 2 mGluRs alone is not sufficient to produce slow-onset potentiation. As (S)-4C3H-PG is also an antagonist of group 1 mGluRs (Hayashi et al., 1994), one cannot rule out the development of a different response when an interaction between both receptor types is possible. However, it has been

Slow-onset potentiation

is induced by group 1 mGluR agonists

that application of other group 2 mGluR agonists also results in depression of hippocampal basal synaptic transmission (Holscher et al., 1997; Huang et al., 1997). The finding that (S)-4C3H-PG decreases basal synaptic transmission is consistent with the reports of others that group 2 mGluRs play a role in inhibition of basal synaptic transmission, possibly through presynaptic inhibition of transmitter release (Vign.es et al., 1995), and suggests that these receptors are unlikely candidates for a role in slowonset potentiation. This finding does not rule out the possibility that group 2 mGluRs play a role in other forms of synaptic plasticity, however. Recently, it was shown that whereas antagonism. of group 2 mGluRs results in an inhibition of long-term depression (LTD) in freely moving rats, no effect on LTP is seen (ManahanVaughan, 1997). Similar reports with regard to group 2 mGluR involvement in LTD have been made in vitro, combined with the observation that group 2 mGluR agonists inhibit LTP (Huang et al., 1997). These findings would suggest a differential role for group 2 mGluRs in synaptic plasticity. Thus group 2 mGluRs may act as modulators of the induction threshold for LTP, but may be a critical factor in LTD induction. In conclusion, this study indicates that slow-onset potentiation in the CA1 region is mediated by activation of group 1 mGluRs, whereas stimulation of group 2 mGluRs does not appear to contribute significantly to this phenomenon. These data offer further insight into the delicate functional interplay of mGluRs in synaptic plasticity, and support the differential involvement of group 1 mGluRs in slow-onset potentiation in viva. reported

Acknowledgements-The authors would like to thank MS Silvia Vieweg for her valuable assistance in technical aspects of this work. This work was suplported in part by a grant to K.G.R. from the European Biorned II programme (BMH4-CT960228).

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