@article{99394cfae29940de89caf444a6e5fdbe,
title = "Pharmacology of metabotropic glutamate receptors at the mossy fiber synapses of the guinea pig hippocampus",
abstract = "We have tested the ability of several specific agonists of glutamate metabotropic receptors (mGluRS) to depress synaptic transmission at mossy fiber synapses in the CA3 region of the guinea pig hippocampus. 1S,3R-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD) reversibly inhibited monosynaptic mossy fiber field potentials, presumably by a presynaptic mechanism, with an EC50 of 2.0 ± 0.4 μM (n = 3), suggesting the presence of mGluRs on mossy fiber synaptic terminals of the group 1 or 2 category. l-2-amino-4-phosphono butanoate (L-AP4) also inhibited responses with an EC50 of 1.1 ± 0.2 μM suggesting that mGluRs of the group 3 (mGluR4, 6, 7 and 8) category of receptors are also present on mossy fiber terminals. Both (2S,1′S,2′S)-2-(2′-carboxycyclopropyl)glycine (L-CCG1) and (S)-4-carboxy-3-hydroxy phenylglycine (4C3HPG) were also efficacious at blocking mossy fiber transmission, with an EC50 of 1.1 ± 0.1 μM (n = 4) and 4.8 ± 0.6 μM (n = 3) respectively. The latter finding indicates the involvement of mGluRS belonging to the group 2 (mGluR2, 3) category of receptors. The effects of L-AP4 and L-CCG1 were both antagonized by (+)-α-methyl-4-carboxyphenylglycine [(+)MCPG]. MAP4, an antagonist of group 3 mGluRs in other systems, blocked the effect of L-AP4, but not the effect of L-CCG1, while MCCG, an antagonist of group 2 mGluRs in other systems, blocked the effect of L-CCG1, but not the effect of L-AP4. These pharmacological findings provide strong evidence for the coexistence of group 2 and 3 mGluRs on the terminals of mossy fibers in the guinea pig.",
keywords = "ACPD, CA3, Hippocampus, L-AP4, metabotropic glutamate receptors, mossy fiber, phenylglycines",
author = "Manzoni, {O. J.} and Castillo, {P. E.} and Nicoll, {R. A.}",
note = "Funding Information: of mossy fibers to L-AP4 is more consistent with an receptor,m GluR1, in transfectedCHO cells. Neuron 8: mGluR4 subtype. 757-765. Expressiono f singler eceptorc lonesi n animalc ellsh as BashirZ . I., BortolottoZ . A., DaviesC . H., BerrettaN ., Irving enabled the determinationo f the selectivitya nd the A. J., SealA . J., HenleyJ . M., Jane D. F., Watkins J. C. and potency of new agonistsa nd antagonistsa t mGluRs Collingridge G. L. (1993)I nduction of LTP in the hippo- (Hayashi et al., 1992,1 994;T homsen et al., 1994).I n receptorsN. ature 363: 347-350. campusn eedss ynaptica ctivationo f glutamatem etabotropic particular theses tudiesh ave shown that L-CCGl is a BaskysA . and Malenka R. C. (1991)A gonistsa t metabotropic selectivea gonista t receptorso f the group 2 category( at glutamater eceptorsp resynapticallyin hibit EPSCs in neo- micromolar concentrationsa) nd that 4C3HPG is both natal rat hippocampusJ.. Physiol. 444: 687-701. an agonist at group 2 receptorsa nd an antagonista t Bushel1T . J., Jane D. E., Tse H.-W., Watkins J. C., Davies receptorsb elonging to group 1. In our hands, both C. H., GarthwaiteJ . and CollingridgeG . L. (1995)A ntagon-compoundsp roved to be effectivew, ith EC,,s in the low ism of thes ynapticd epressanat ctionso f L-AP4 in thel ateral micromolar range. This data with selectivea gonists perforantp ath by MAP4. Neuropharmacolog3y4 : 239-241. suggeststh at, in addition to the presenceo f a group 3 Cotman C. W., Flatman J. A., Ganong A. H. and Perkins mGluR, a group 2 mGluR (Tanabee t al., 1992)i s also M. N. (1986)E ffectso f excitatorya mino acid antagonistso n presento n mossyf iber synaptict erminals. evokeda nd spontaneouse xcitatoryp otentialsi n guineap ig We extendedt he agonist studiesb y examiningt he hippocampusJ.. Physiol. 378:4 03-415. effects of various mGluR antagonists.R ecently, the mate receptors depress excitatory monosynaptic trans-Forsythe I. D. and ClementsJ . D. (1990)P resynapticg luta- action of MCPG, an antagonisto f mGluRs, has been mission betweenm ouseh ippocampaln eurones.J . Physiot. studied in the hippocampals lice (Bashir et al., 1993; 429: l-16. Manzoni et al., 1994),a nd pharmacologicasl tudieso n Harris E. W. and Cotman W. E. (1983)E ffectso f acidica mino cloned receptors suggestedt hat MCPG was inactive acid antagonistso n paired-pulsep otentiationa t the lateral (IC,, > 1 mM) at mGluR4 receptors (Hayashi et al., perforantp ath. Exp. Brain Res. 52: 455460. 1994;T homsene t al., 1994)b ut is activea t most other Hayashi Y., Tanabe Y., Aramori I., Masu M. J., Shimamoto mGluRs. We thereforet estedt he effects( +)MCPG, the K., Ohfune Y. and Nakanishi S. (1992)A gonist analysiso f activef orm of MCPG (Jane et al., 1993)o n both L-APC 2-(carboxycyclopropyl)glyciniseo mersf or cloned metabo- and L-CCGl-induced depressiona nd found (+)MCPG tropic glutamater eceptor subtypese xpressedin Chinese to be effectivei n blocking both L-APC and L-CCGl-hamstero vary cells. Br. J. Pharmac.1 07: 539-543. inducede ffects.T his finding suggesttsh at, althought he D. C., Birse E. F., Udvarhelyi P. M. and Watkins J. C. Hayashi Y., SekiyamaN ., Nakanishi S., Jane D. E., Sunter group 3 mGluR on mossy fiber terminalsh as a high (1994) Analysis of agonist and antagonist activities of affinity for L-AP4, the depressioni s unlikely to be phenylglycined erivativesf or differentc loned metabotropic mediatedb y an mGluR4. MAP4 selectivelyb lockedt he glutamater eceptors ubtypes.J . Neurosci. 14: 337&3377. actionso f L-AP4, while MCCG selectivelya ntagonized Jane D. E., Jones P. L. S. J., Pook P. C.-K., Tse H.-W. and the action of L-CCGl. These antagonists tudiese xtend Watkins J. C. (1994)A ctions of two new antagonistss how-the agonists tudiesa nd clearly indicatet hat guineap ig ing selectivityf or differents ub-typeso f metabotropicg luta-mossyf iber terminalse xpressm GluRs of group 2 and 3. mate receptor in the neonatal rat spinal cord. Br. J. Our resultsc ompliments tudieso n the spinalc ord of the Pharmac.1 12: 809-81 6. newbornr at in which similarp harmacologicael vidence Jane D. E., Jones P. L. S. J., Pook P. C.-K., Salt T. E., Sunter suggeststh e presenceo f group 2 and 3 mGluRs on the D. C. and Watkins J. C. (1993)S tereospecifiacn tagonismb y terminalso f primary afferentf ibers (Jane et al., 1994). (+)-a -methyl-4-carboxyphenylglycin(Me CPG) of (1S ,3R)- In conclusion, we have provided pharmacological thalamicn eurones.N europharmacolog3y2 : 725-727. ACPD-induced effectsin neonatalr at motoneuronesa nd rat evidencefo r thei nvolvemenot f two subtypeso f mGluRs Kristensen P., Suzdak P. D. and Thomsen C. (1993) Ex- in the depressiono f mossy fiber synaptict ransmission. pression pattern and pharmacologyo f the rat type IV While our results indicate that both group 2 and 3 metabotropic glutamate receptor. Neurosci. Lett. 155: mGluRs participatei n this depressionw, e were unable 159-162. to identifyd efinitivelyw hich specificm GluR within each Lanthorn T. H., Ganong A. H. and Cotman C. W. (1984) group was responsiblefo r the inhibition. Further devel- 2-amino-4-phosphonobutyrates electively blocks mossy opmento f subtype-specifiacg onistsa nd antagonistsw ill fiber-CA3 responseisn guineap ig but not rat hippocampus. be neededt o unequivocallya ddresst hesei ssues. Brain Res. 290: 174-178. Manzoni 0. J., Weisskopf M. G. and Nicoll R. A. (1994) Acknowledgements-Thisresearchwas supported by the MCPG antagonizesm etabotropicg lutamater eceptorsb ut NIMH. R.A.N. is a memberofthe Keck CenterforIntegrative not long-term potentiation in the hippocampus.E ur. J. Neuroscienceand the Silvio Conte Center for Neuroscience Neurosci.6 : 1050-1054. Research. Manzoni 0. J., Finiels-Marlier F., SassettiI ., BockaertJ ., le Peuch C. and SladeczekF . A. J. (1990) The glutamate",
year = "1995",
month = aug,
doi = "10.1016/0028-3908(95)00060-J",
language = "English (US)",
volume = "34",
pages = "965--971",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "8",
}