Anatomical Distribution of Metabotropic Glutamate Receptors in Mammalian Brain

  • Claudia M. Testa
  • Maria Vincenza Catania
  • Anne B. Young
Part of the The Receptors book series (REC)


Metabotropic glutamate receptors (mGluRs) are linked to second messengers through G-proteins and play an important role in normal neuronal functions, as well as plasticity and response to injury. Until recently, it has not been possible to examine the detailed localization of mGluRs in mammalian brain because of the lack of specific agonists and antagonists amenable to ligand binding studies and the lack of cloned cDNA sequences for the development of specific in situ hybridization probes or antibodies for immunocytochemistry. In the past few years, many of these reagents have become available, yielding data from several avenues that have indicated marked regional heterogeneity in the distributions of mGluR subtypes. In this chapter, we will review the regional expression of the five mGluR genes that have been most thoroughly characterized, the second-messenger systems associated with these receptors, and the autoradiographic binding studies of pharmacological subtypes.


Entorhinal Cortex Metabotropic Glutamate Receptor Subthalamic Nucleus Anatomical Distribution Metabotropic Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abe, T., Sugihara, H., Nawa, H., Shigemoto, R., Mizuno, N., and Nakanishi, S. (1992) Molecular characterization of a novel metabotropic glutamate receptor, mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J. Biol. Chem. 267,13, 361–13, 368.Google Scholar
  2. Albin, R. L., Young, A. B., and Penney, J. B. (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375.PubMedCrossRefGoogle Scholar
  3. Albin, R. L., Aldridge, J. W., Young, A. B., and Gilman, S. (1989) Feline subthalamic nucleus neurons contain glutamate-like but not GABA-like or glycine-like immunoreactivity. Brain Res. 491, 185–188.PubMedCrossRefGoogle Scholar
  4. Albin, R. L., Makowiec, R. L., Hollingsworth, Z., Dure, L. S., Penney, J. B., and Young, A. B. (1992) Excitatory amino acid binding sites in the basal ganglia of the rat: a quantitative autoradiographic study. Neurosci. 46, 35–48.CrossRefGoogle Scholar
  5. Aleppo, G., Pisani, A., Copani, A., Bruno, V., Aronica, E., D’Agata, V., Canonico, P. L., and Nicoletti F. (1992) Metabotropic glutamate receptors and neuronal toxicity. Adv. Exp. Med. Biol. 318, 137–145.PubMedCrossRefGoogle Scholar
  6. Aramori, I. and Nakanishi, S. (1992) Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron 8, 757–765.PubMedCrossRefGoogle Scholar
  7. Aronica, E., Frey, U., Wagner, M., Schroeder, H., Krug, M., Ruthrich, H., Catania, M. V., Nicoletti, F., and Reymann, K. G. (1991) Enhanced sensitivity of “metabotropic” glutamate receptors after induction of long-term potentiation in rat hippocampes. J. Neurochem. 57, 376–383.PubMedCrossRefGoogle Scholar
  8. Bashir, Z. I., Bortolotto, Z. A., Davies, C. H., Berretta, N., Irving, A. J., Seal, A. J., Henley, J. M., Jane, D. E., Watkins, J. C., and Collingridge, G. L. (1993) Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Nature 363, 347–350.PubMedCrossRefGoogle Scholar
  9. Beal, M. F., Finn, S. F., and Brouillet, E. (1993) Evidence for the involvement of metabotropic glutamate receptors in striatal excitotoxin lesions in vivo. Neurodegen. 2, 81–91.Google Scholar
  10. Beckstead, R. M. (1979) An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat. J. Comp. Neurol. 184, 43–62.PubMedCrossRefGoogle Scholar
  11. Bliss, T. V.P. and Collingridge, G. L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39.PubMedCrossRefGoogle Scholar
  12. Brotchie, J. M. and Crossman, A. R. (1991) D-[3H]Aspartate and [14C]GABA uptake in the basal ganglia of rats following lesions in the subthalamic region suggest a role for excitatory amino acid but not GABA-mediated transmission in subthalamic nucleus efferents. Exp. Neurol. 113, 171–181.PubMedCrossRefGoogle Scholar
  13. Calabresi, P., Maj, R., Pisani, A., Mercuri, N. B., and Bernardi G. (1992) Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J. Neurosci. 12, 4224–4233.PubMedGoogle Scholar
  14. Canteras, N. S., Shammah-Lagnado, S. J., Silva, B. A., and Ricardo, J. A. (1990) Afferent connections of the subthalamic nucleus: A combined retrograde and anterograde horseradish peroxidase study in the rat. Brain Res. 513, 43–59.PubMedCrossRefGoogle Scholar
  15. Catania, M. V., de Socarraz, H., Penney, J. B., and Young, A. B. (1994) Metabotropic glutamate receptor heterogeneity in rat brain. Mol. Pharmcol. (in press).Google Scholar
  16. Catania, M. V., Hollingsworth, Z., Penney, J. B., and Young, A. B. (1993) Quisqualate resolves two distinct metabotropic [3H]glutamate binding sites. NeuroRep. 4, 311–313.Google Scholar
  17. Cha, J. H., Makowiec, R. L., Penney, J. B., and Young, A. B. (1990) L-[3H]glutamate labels the metabotropic excitatory amino acid receptor in rodent brain. Neurosci. Let. 113, 78–83.CrossRefGoogle Scholar
  18. Choi, D. W. and Rothman, S. M. (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Ann. Rev. Neurosci. 13, 171–182.PubMedCrossRefGoogle Scholar
  19. Condorelli, D. F., Dell’ Albani, P., Amico, C., Casabona, G., Genazzani, A. A., Sortino, M. A., and Nicoletti, F. (1992) Developmental profile of metabotropic glutamate receptor mRNA in rat brain. Mol. Pharmacol. 41, 660–664.PubMedGoogle Scholar
  20. Fotuhi, M., Sharp, A. H., Glatt, C. E., Hwang, P. M., von Krosigk, M., Snyder, S. H., and Dawson, T. M. (1993) Differential localization of phosphoinositide-linked metabotropic glutamate receptor (mGluR1) and the inositol 1,4,5-trisphosphate receptor in rat brain. J. Neurosci. 13, 2001–2012.PubMedGoogle Scholar
  21. Fotuhi, M., Standaert, D. G., Testa, C. M., Penney, J. B., and Young, A. B. (1994) Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat. Mol. Brain Res. 21, 283–292.PubMedCrossRefGoogle Scholar
  22. Gabellini, N., Manev, R. M., Candeo, P., Favaron, M., and Manev, H. (1993) Carboxyl domain of glutamate receptor directs its coupling to metabolic pathways. NeuroRep. 4, 531–534.Google Scholar
  23. Greenamyre, J. T., Higgins, D. S., Young, A. B., and Penney, J. B. (1990) Regional ontogeny of a unique glutamate recognition site in rat brain: an autoradiographic study. Int. J. Dey. Neurosci. 8, 437–445.CrossRefGoogle Scholar
  24. Groenewegen, H. J. and Berendse, H. W. (1990) Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat. J. Comp. Neurol. 294, 607–622.PubMedCrossRefGoogle Scholar
  25. Hayashi, Y., Tanabe, Y., Aramon, I., Masu, M., Shimamoto, K., Ohfune, Y., and Nakanishi, S. (1992) Agonist analysis of 2-(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate receptor subtypes expressed in Chinese hamster ovary cells. Br. J. Pharmacol. 107, 539–543.PubMedCrossRefGoogle Scholar
  26. Houamed, K. M., Kuijper, J. L., Gilbert, T. L., Haldeman, B. A., O’Hara, P. J., Mulvihill, E. R., Almers, W., and Hagen, F. S. (1991) Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. Science 252, 1318–1321.PubMedCrossRefGoogle Scholar
  27. Hwang, P. M., Bredt, D. S., and Snyder, S. H. (1990) Autoradiographic imaging of phosphoinositide turnover in the brain. Science 249, 802–804.PubMedCrossRefGoogle Scholar
  28. Ito, M., Sakurai, M., and Tongroach, P. (1982) Climbing fibre induced depression of both mossy fiber responsiveness and glutamate sensitivity of cerebellar Purkinje cells. J. Physiol. 324, 113–134.PubMedGoogle Scholar
  29. Kano, M. and Kato, M. (1987) Quisqualate receptors are specifically involved in cerebellar synaptic plasticity. Nature 325, 276–279.PubMedCrossRefGoogle Scholar
  30. Kim, J. S., Hassler, R., Haug, P., and Paik, K. S. (1977) Effect of frontal cortex ablation on striatal glutamic acid level in the rat. Brain Res. 132, 370–374.PubMedCrossRefGoogle Scholar
  31. Kita, H. and Kitai, S. T. (1987) Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method. J. Comp. Neurol. 260, 435–452.PubMedCrossRefGoogle Scholar
  32. Lee, H. J., Rye, D. B., Hallanger, A. E., Levey, A. I., and Wainer, B. H. (1988) Cholinergic vs. noncholinergic efferents from the mesopontine tegmentum to the extrapyramidal motor system nuclei. J. Comp. Neurol. 275, 469–492.PubMedCrossRefGoogle Scholar
  33. Linden, D. J., Dickinson, M. H., Smeyne, M., and Connor, J. A. (1991) A long-term depression of AMPA currents in cultured cerebellar Purkinje neurons. Neuron 7, 81–89.PubMedCrossRefGoogle Scholar
  34. Martin, L. J., Blackstone, C. D., Huganir, R. L., and Price, D. L. (1992) Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron 9, 259–270.PubMedCrossRefGoogle Scholar
  35. Masu, M., Tanabe, Y., Tsuchida, K., Shigemoto, R., and Nakanishi, S. (1991) Sequence and expression of a metabotropic glutamate receptor. Nature 349, 760–765.PubMedCrossRefGoogle Scholar
  36. McDonald, J. W. and Schoepp, D. D. (1992) The metabotropic excitatory amino acid receptor agonist 1S,3R-ACPD selectively potentiates N-methyl-o-aspartateinduced brain injury. Eur. J. Pharmacol. 215, 353, 334.Google Scholar
  37. McGeer, P. L., McGeer, E. G., Scherer, U., and Singh, K. (1977) A glutamatergic corticostriatal path? Brain Res. 128, 369–373.PubMedCrossRefGoogle Scholar
  38. Minakami, R., Katsuki, F., and Sugiyama, H. (1993) A variant of metabotropic glutamate receptor subtype 5: an evolutionally conserved insertion with no termination codon. Biochem. Biophys. Res. Commun. 194, 622–627.PubMedCrossRefGoogle Scholar
  39. Nakajima, Y., Iwakabe, H., Akazawa, C., Nawa, H., Shigemoto, R., and Mizuno, N. (1993) Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2- amino-4- phosphonobutyrate. J. Biol. Chem. 268, 11,868–11, 873.Google Scholar
  40. Nakanishi, H., Kita, H., and Kitai, S. T. (1987) Intracellular study of rat substantia nigra pars reticulata neurons in an in vitro slice preparation: electrical membrane properties and response characteristics to subthalamic stimulation. Brain Res. 437, 45–55.PubMedCrossRefGoogle Scholar
  41. Nakanishi, S. (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597–603.PubMedCrossRefGoogle Scholar
  42. Nicoletti, F., Iadarola, M. J., Wroblewski, J. T., and Costa, E. (1986) Excitatory amino acid recognition sites coupled with inositol phospholipid metabolism: developmental changes and interaction with a1-adrenoreceptors. Proc. Natl. Acad. Sci. USA 83, 1931–1935.PubMedCrossRefGoogle Scholar
  43. Nicoletti, F., Wroblewski, J. T., Alho, H., Eva, C., Fadda, E., and Costa, E. (1987) Lesions of putative glutamatergic pathways potentiate the increase of inositol phospholipid hydrolysis elicited by excitatory amino acids. Brain Res. 436, 103–112.PubMedCrossRefGoogle Scholar
  44. Ohishi, H., Shigemoto, R., Nakanishi, S., and Mizuno, N. (1993a) Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neurosci. 53, 1009–1018.CrossRefGoogle Scholar
  45. Ohishi, H., Shigemoto, R., Nakanishi, S., and Mizuno, N. (1993b) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the brain: an in situ hybridization study. J. Comp. Neurol. 335, 252–266.PubMedCrossRefGoogle Scholar
  46. Pickering, D. S., Thomsen, C., Suzdak, P. D., Fletcher, E. J., Robitaille, R., Salter, M. W., MacDonald, J. F., Huang, X.-P., and Hampson, D. R. (1993) A comparison of two alternatively spliced forms of a metabotropic glutamate receptor coupled to phosphoinositide turnover. J. Neurochem. 61, 85–92.PubMedCrossRefGoogle Scholar
  47. Pin, J. P., Waeber, C., Prezeau, L., Bockaert, J., and Heinemann, S. F. (1992) Alternative splicing generates metabotropic glutamate receptors inducing different patterns of calcium release in Xenopus oocytes. Proc. Natl. Acad. Sci. USA 89, 10,331–10, 335.Google Scholar
  48. Price, R. H., Hollingsworth, Z., Young, A. B., and Penney, J. B. (1993) Excitatory amino acid receptor regulation after subthalamic nucleus lesions in the rat. Brain Res. 602, 157–160.PubMedCrossRefGoogle Scholar
  49. Robledo, P. and Feger, J. (1990) Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiological data. Brain Res. 518, 47–54.PubMedCrossRefGoogle Scholar
  50. Sacaan, A. I. and Schoepp, D. D. (1992) Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage. Neurosci. Lett. 139, 77–82.PubMedCrossRefGoogle Scholar
  51. Sacaan, A. I., Monn, J. A., and Schoepp, D. D. (1991) Intrastriatal injection of a selective metabotropic excitatory amino acid receptor agonist induces contralateral turning in the rat. J. Pharmacol. Exp. Ther. 259, 1366–1370.PubMedGoogle Scholar
  52. Sacaan, A. I., Bymaster, F. P., and Schoepp, D. D. (1992) Metabotropic glutamate receptor activation produces extrapyramidal motor system activation that is mediated by dopamine. J. Neurochem. 59, 245–251.PubMedCrossRefGoogle Scholar
  53. Seren, M. S., Aldinio, C., Zanoni, R., Leon, A., and Nicoletti, F. (1989) Stimulation of inositol phospholipid hydrolysis by excitatory amino acids is enhanced in brain slices from vulnerable regions after transient global ischemia. J. Neurochem. 53, 1700–1705.PubMedCrossRefGoogle Scholar
  54. Shigemoto, R., Nakanishi, S., and Mizuno, N. (1992) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in adult and developing rat. J. Comp. Neurol. 322, 121–135.PubMedCrossRefGoogle Scholar
  55. Sladeczak, F., Pin, J.-P., Récasens, M., Bockaert, J., and Weiss, S. (1985) Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 317, 717–719.CrossRefGoogle Scholar
  56. Smith, Y. and Parent A. (1988) Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity. Brain Res. 453, 353–356.PubMedCrossRefGoogle Scholar
  57. Standaert, D. G., Testa, C. M., Penney, J. B., and Young, A. B. (1993) Alternatively spliced isoforms of the NMDARI glutamate receptor: differential expression in the basal ganglia of the rat. Neurosci. Lett. 152, 161–164.PubMedCrossRefGoogle Scholar
  58. Sugiyama, H., Ito, I., and Hirono C. (1987) A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325, 531–533.PubMedCrossRefGoogle Scholar
  59. Tanabe, Y., Masu, M., Ishii, T., Shigemoto, R., and Nakanishi, S. (1992) A family of metabotropic glutamate receptors. Neuron 8, 169–179.PubMedCrossRefGoogle Scholar
  60. Tanabe, Y., Nomura, A., Masu, M., Shigemoto, R., Mizuno, N., and Nakanishi S. (1993) Signal transduction, pharmacologic properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J. Neurosci. 13, 1372–1378.PubMedGoogle Scholar
  61. Testa, C. M., Standaert, D. G., Young, A. B., and Penney, J. B. (1994) Metabotropic glutamate receptor expression in the basal ganglia of the rat. J. Neurosci. in press.Google Scholar
  62. Winder, D. G. and Conn, P. J. (1993) Activation of metabotropic glutamate receptors increases cAMP accumulation in hippocampus by potentiating responses to endogenous adenosine. J. Neurosci. 13, 38–44.PubMedGoogle Scholar
  63. Worley, P. F., Baraban, J. M., and Snyder, S. H. (1989) Inositol 1,4,5-trisphosphate receptor binding: autoradiographic localization in rat brain. J. Neurosci. 9, 339–346.PubMedGoogle Scholar
  64. Worley, P. F., Baraban, J. M., De Souza, E. B., and Snyder, S. H. (1986a) Mapping second messenger systems in the brain: differential localizations of adenylyl cyclase and protein kinase C. Proc. Natl. Acad. Sci. USA 83, 4053–4057.PubMedCrossRefGoogle Scholar
  65. Worley, P. F., Baraban, J. M., and Snyder, S. H. (1986b) Heterogeneous localization of protein kinase C in rat brain: autoradiographic analysis of phobol ester receptor binding. J. Neurosci. 6, 199–207.PubMedGoogle Scholar
  66. Young, A. B., Bromberg, M. B., and Penney, J. B. (1981) Decreased glutamate uptake in subcortical areas deafferented by sensorimotor cortical ablation in the cat. J. Neurosci. 1, 241–249.PubMedGoogle Scholar
  67. Young, A. B. and Fagg, G. E. (1990) Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches. Trends Pharmacol. Sci. 11, 126–133.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Claudia M. Testa
  • Maria Vincenza Catania
  • Anne B. Young

There are no affiliations available

Personalised recommendations