Long-Lasting Modulation of Synaptic Transmission by Metabotropic Glutamate Receptors

  • Joel P. Gallagher
  • Fang Zheng
  • Patricia Shinnick-Gallagher
Part of the The Receptors book series (REC)


Studies of the functional roles for metabotropic glutamate receptors (mGluRs) in the central nervous system have rapidly developed over the past two years. mGluR agonists have a diverse range of electrophysiological effects, including long-lasting modulation of synaptic transmission. Putative mGluR antagonists l-2- amino-4-phosphonobutyrate (L-AP4) and/or 2-amino-3-phosphonopropionic acid (AP3) blocked the induction or/and maintenance of long-term potentiation (LTP) in the hippocampal CA1 region (Reymann and Matthies, 1989; Izumi et al., 1991) and the dorsolateral septal nucleus (DLSN) of rat (Zheng and Gallagher, 1990). Phospholipase C (PLC)-coupled mGluRs may also play a role in the induction of long-term depression in cerebellar Purkinje neurons (Linden et al., 1991; Daniel et al., 1992). In addition to the long-lasting modulation of synaptic transmission, mGluRs might also play a role in the pathogenesis of epilepsy. In this chapter, we will review the current data and discuss the problems encountered in this field.


Synaptic Transmission Mossy Fiber Metabotropic Glutamate Receptor Basolateral Amygdala Burst Firing 
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/Ca’ signal transduction. J. Biol. Chem. 267, 13,361–13, 368.Google Scholar
  2. Akiyama, K., Yamada, N., and Otsuki, S. (1989) Lasting increase in excitatory amino acid receptor-mediated polyphosphoionositide hydrolysis in the amygdala/pyriform cortex of amygdala-kindled rats. Brain Res. 485, 95–101.PubMedCrossRefGoogle Scholar
  3. Akiyama, K., Yamada, N., and Sato, M. (1987) Increase in ibotenate-stimulated phosphatidylinositol hydrolysis in slices of the amygdala/pyriform cortex and hippocampus of rat by amygdala kindling. Exp. Neurol. 98, 499–508.PubMedCrossRefGoogle Scholar
  4. Akiyama, K., Daigen, A., Yamada, N., Itoh, T., Kohira, I., Ujike, H., and Otsuki, S. (1992) Long-lasting enhancement of metabotropic excitatory amino acid receptor-mediated polyphosphoinositide hydrolysis in the amygdala/pyriform cortex of deep pyriform cortical kindled rats. Brain Res. 569, 72–77.Google Scholar
  5. Aniksztejn, L., Otani, S., and Ben-Ari, Y. (1992) Quisqualate metabotropic receptors modulate NMDA currents and facilitate induction of long-term potentiation through protein kinase C. Eur. J. Neurosci. 4, 500–505.PubMedCrossRefGoogle Scholar
  6. Artola, A. and Singer, W. (1987) Long-term potentiation and NMDA receptors in rat visual cortex. Nature 330, 649–652.PubMedCrossRefGoogle Scholar
  7. 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. (1993a) Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Nature 363, 347–350.Google Scholar
  8. Bashir, Z. I., Jane, D. E., Sunter, D. C., Watkins, J. C., and Collingridge, G. L. (1993b) Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus. Eur. J. Pharmacol. 239, 265, 266.Google Scholar
  9. Baskys, A. and Malenka, R. C. (1991) Trans-ACPD depresses synaptic transmission in the hippocampus. Eur. J. Pharmacol. 193, 131, 132.Google Scholar
  10. Behnisch, T. and Reymann, K. G. (1993) Co-activation of metabotropic glutamate and N-methyl-D-aspartate receptors is involved in mechanisms of long-term potentiation maintenance in rat hippocampal CA1 neurons. Neuroscience 54, 37–47.PubMedCrossRefGoogle Scholar
  11. Bliss, T. V. P. and Lomo, T. (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbits following stimulation of the perforant path. J. Physiol. (Lond.) 232, 331–356.Google Scholar
  12. Bortolotto, Z. A. and Collingridge, G. L. (1992) Activation of glutamate metabotropic receptors induces long-term potentiation. Eur. J. Pharmacol. 214, 297, 298.Google Scholar
  13. Bortolotto, Z. A. and Collingridge, G. L. (1993) Characterisation of LTP induced by the activation of glutamate metabotropic receptors in area CA1 of the hippocampus. Neuropharmacology 32, 1–9.PubMedCrossRefGoogle Scholar
  14. Boss, V. and Conn, P. J. (1992) Metabotropic excitatory amino acid receptor activation stimulates phospholipase D in hippocampal slices. J. Neurochem. 59, 2340–2343.PubMedCrossRefGoogle Scholar
  15. Cain, D. P. (1989) Long-term potentiation and kindling: how similar are the mechanisms. Trends Neurosci. 12, 6–10.PubMedCrossRefGoogle Scholar
  16. 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
  17. Collingridge, G. L., Kehl, S. J., and McLennan, H. (1983) Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J. Physiol. (Lond.) 334, 33–46.Google Scholar
  18. Collins, D. R. and Davies, S. N. (1993) Co-administration of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid and arachidonic acid potentiates synaptic transmission in rat hippocampal slices. Eur. J. Pharmacol. 240, 325, 326.Google Scholar
  19. Daniel, H., Hemart, N., Jaillard, D., and Crepel, F. (1992) Coactivation of metabotropic glutamate receptors and of voltage-gated calcium channels induces long-term depression in cerebellar Purkinje cells in vitro. Exp. Brain Res. 90, 327–331.PubMedCrossRefGoogle Scholar
  20. Desai, M. A. and Conn, P. J. (1991) Excitatory effects of ACPD receptor activation in the hippocampus are mediated by direct effects on pyramidal cells and blockade of synaptic inhibition. J. Neurophysiol. 66, 40–52.PubMedGoogle Scholar
  21. Douglas, R. M. and Goddard, G. V. (1975) Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus. Brain Res. 86, 205–215.PubMedCrossRefGoogle Scholar
  22. Frenguelli, B. G., Potier, B., Slater, N. T., Alford, S., and Collingridge, G. L. (1994) Metabotropic glutamate receptors and calcium signalling in dentrites of hippocampal CA1 neurons. Neuropharmacol. 32, 1229–1237.CrossRefGoogle Scholar
  23. Gallagher, J. P. and Zheng, F. (1993) Distinct subtypes of pertussis toxin-resistant metabotropic glutamate receptors at rat dorsolateral septal nucleus neurons. Soc. Neurosci. Abstr. 19, 470.Google Scholar
  24. Gean, P. W., Shinnick-Gallagher, P., and Anderson, A. C. (1989) Spontaneous epileptiform activity and alteration of GABA- and NMDA-mediated neurotransmission in amygdala neurons kindled in vivo. Brain Res. 494, 171–181.Google Scholar
  25. Goddard, G. V., McIntyre, D. C., and Leech, C. K. (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurol. 25, 295–330.PubMedCrossRefGoogle Scholar
  26. Goddard, G. V., McNaughton, B. L., Douglas, R. M., and Barnes, C. A. (1978) Synaptic change in the limbic system; evidence from studies using electrical stimulation with and without seizure activity, in The Continuing Evolution of the Limbic System Concept ( Livingston, K. and Hornykiewicz, O., eds.), Plenum, New York, pp. 355–368.Google Scholar
  27. Goh, J. W. and Pennefather, P. S. (1989) A pertussis toxin-sensitive G protein in hippocampal long-term potentiation. Science 244, 980–983.PubMedCrossRefGoogle Scholar
  28. Grover, L. M. and Teyler, T. J. (1990) Two components of long-term potentiation induced by different patterns of afferent activation. Nature 347, 477–479.PubMedCrossRefGoogle Scholar
  29. Harris, E. W. and Cotman, C. W. (1986) Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists. Neurosci. Lett. 70, 132–137.PubMedCrossRefGoogle Scholar
  30. Harris, E. W., Ganong, A. H., and Cotman, C. W. (1984) Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors. Brain Res. 323, 132–137.PubMedCrossRefGoogle Scholar
  31. Harvey, J. and Collingridge, G. L. (1993) Signal transduction pathways involved in the acute potentiation of NMDA responses by 1S,3R-ACPD in rat hippocampal slices. Br. J. Pharmacol. 109, 1085–1090.PubMedCrossRefGoogle Scholar
  32. Iadorola, M. J., Nicoletti, F., Naranjo, J. R., Putnam, F., and Costa, E. (1986) Kindling enhances the stimulation of inositol. Brain Res. 374, 174–178.PubMedCrossRefGoogle Scholar
  33. Ito, I. and Sugiyama, H. (1991) Roles of glutamate receptors in long-term potentiation at hippocampal mossy fiber synapses. Neuroreport 2, 333–336.PubMedCrossRefGoogle Scholar
  34. Ito, I., Okada, D., and Sugiyama, H. (1988) Pertussis toxin suppresses long-term potentiation of hippocampal mossy fiber synapses. Neurosci. Lett. 90, 181–185.PubMedCrossRefGoogle Scholar
  35. Izumi, Y., Clifford, D. B., and Zorumski, C. F. (1991) 2-Amino-3-phosphonopropionate blocks the induction and maintenance of long-term potentiation in rat hippocampal slices. Neurosci. Lett. 122, 187–190.Google Scholar
  36. Johnston, D., Williams, S., Jaffe, D., and Gray, R. (1992) NMDA-receptor-independent long-term potentiation. Ann. Rev. Physiol. 54, 489–505.CrossRefGoogle Scholar
  37. Kano, M. and Kato, M. (1987) Quisqualate receptors are specifically involved in cerebullar synaptic plasticity. Nature 325, 276–279.PubMedCrossRefGoogle Scholar
  38. Kato, N. (1993) Dependence of long-term depression on postsynaptic metabotropic glutamate receptors in visual cortex. Proc. Natl. Acad. Sci. USA 90, 36503654.Google Scholar
  39. Katsuki, H., Kaneko, S., and Satoh, M. (1992) Involvement of postsynaptic G proteins in hippocampal long-term potentiation. Brain Res. 581, 108–114.PubMedCrossRefGoogle Scholar
  40. 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
  41. Lynch, G., Larson, J., Kelso, S., Barrionuevo, G., and Schottler, F. (1983) Intracellular injection of EGTA block induction of hippocampal long-term potentiation. Nature 305, 719–721.Google Scholar
  42. 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
  43. McGuinness, N., Anwyl, R., and Rowan, M. (1991a) The effects of trans-ACPD on long-term potentiation in the rat hippocampal slice. Neuroreport 2, 688–690.PubMedCrossRefGoogle Scholar
  44. McGuinness, N., Anwyl, R., and Rowan, M. (1991b) Trans-ACPD enhances longterm potentiation in the hippocampus. Eur. J. Pharmacol. 197, 231, 232.Google Scholar
  45. McNamara, J. O., Rigsbee, L. C., Butler, L. S., and Shin, C. (1989) Intravenous phenytoin is an effective anticonvulsant in the kindling model. Ann. Neurol. 26, 676–678.CrossRefGoogle Scholar
  46. Morris, R. G. M., Anderson, E., Lynch, G. S., and Baudry, M. (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-Daspartate receptor antagonist, AP5. Nature 319, 774–776.PubMedCrossRefGoogle Scholar
  47. Murphy, S. N. and Miller, R. J. (1988) A glutamate receptor regulates Ca’ mobilization in hippocampal neurons. Proc. Natl. Acad. Sci. USA 85, 8737–8741.PubMedCrossRefGoogle Scholar
  48. O’Connor, J. J., Rowan, M. J., and Anwyl, R. (1993a) Long-lasting potentiation of the NMDA receptor-mediated EPSC is inhibited by metabotropic glutamate receptor antagonists in rat dentate granule cells in vitro. J. Physiol. (Lond.) 473, 170 P.Google Scholar
  49. O’Connor, J. J., Rowan, M. J., and Anwyl, R. (1993b) Potentiation of NMDA receptor-mediated excitatory postsynaptic currents following metabotropic glutamate receptor activation and tetanic stimulation in rat hippocampus. J. Physiol. (Lond.) 473, 47 P.Google Scholar
  50. Ohishi, H., Shigemoto, R., Nakamishi, S., and Mizuno, N. (1993) Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system. Neuroscience 53, 1009–1018.PubMedCrossRefGoogle Scholar
  51. Ohishi, H., Shigemoto, R., Nakamishi, S., and Mizuno, N. (1993) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain. J. Comp. Neurol. 335, 252–266.PubMedCrossRefGoogle Scholar
  52. Otani, S. and Ben-Ari, Y. (1991) Metabotropic receptor-mediated long-term potentiation in rat hippocampal slices. Eur. J. Pharmacol. 205, 325, 326.Google Scholar
  53. Otani, S., Ben-Ari, Y., and Roisin-Lallemand, M.-P. (1993) Metabotropic receptor stimulation coupled to weak tetanus leads to long-term potentiation and a rapid elevation of cytosolic protein kinase C activity. Brain Res. 613, 1–9.PubMedCrossRefGoogle Scholar
  54. Racine, R. (1972) Modification of seizure activity by electrical stimulation: I. After- discharge threshold. Electroencephalogr. Clin. Neurophysiol 32, 269–279.PubMedCrossRefGoogle Scholar
  55. Radpour, S. and Thomson, A. M. (1992) Synaptic enhancement induced by NMDA and Q receptors and presynaptic activity. Neurosci. Lett. 138, 119–122.PubMedCrossRefGoogle Scholar
  56. Rainnie, D. G. and Shinnick-Gallagher, P. (1992) Activation of postsynaptic metabotropic receptors by trans-ACPD evokes a membrane hyperpolarization in neurons of the basolateral amygdala. Soc. Neurosci. Abstr. 22, 266.Google Scholar
  57. Rainnie, D. G., Asprodini, E., and Shinnick-Gallagher, P. (1992) Kindling-induced long-lasting changes in excitatory and inhibitory transmission in the basolateral amygdala. J. Neurophysiol. 67, 443–454.PubMedGoogle Scholar
  58. Rainnie, D. G., Holmes, K. H. and Shinnick-Gallagher, P. (1994) Activation of postsynaptic metabotropic glutamate receptors by trans-ACPD hyperpolarizes neurones of the basolateral amygdala. J. Neurosci.,in press.Google Scholar
  59. Reymann, K. G. and Matthies, H. (1989) 2-Amino-4-phosphonobutyrate selectively eliminates late phases of long-term potentiation in rat hippocampus. Neurosci. Lett. 98, 166–171.Google Scholar
  60. Riedel, G. and Reymann, K. (1993) An antagonist of the metabotropic glutamate receptor prevents LTP in the dentate gyrus of freely moving rats. Neuropharmacology 32, 929–931.PubMedCrossRefGoogle Scholar
  61. 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
  62. Sato, M., Racine, R. J., and McIntyre, D. C. (1990) Kindling: basic mechanisms and clinical validity. Electroencephalogr. Clin. Neurophysiol 76, 459–472.PubMedCrossRefGoogle Scholar
  63. Savage, D. D., Werling, L. L., Nadler, J. V., and McNamara, J. O. (1984) Selective and reversible increase in the number of quisqualate-sensitive glutamate binding sites on hippocampal synaptic membranes after angular bundle kindling. Brain Res. 307, 332–335.PubMedCrossRefGoogle Scholar
  64. Schmidt, J. T. (1990) Long-term potentiation and activity-dependent retinotopic sharpening in the regenerating retinotectal projection of goldfish: common sensitive period and sensitivity to NMDA blockers. J. Neurosci. 10, 233–246.PubMedGoogle Scholar
  65. Schoepp, D. D. and Johnson, B. G. (1988) Excitatory amino acid agonist-antagonist interactions at 2-amino-4-phosphonobutyric acid-sensitive quisqualate receptors coupled to phosphoinositide hydrolysis in slices of rat hippocampus. J. Neurochem. 50, 1605–1613.PubMedCrossRefGoogle Scholar
  66. Schoepp, D. D. and Johnson, B. G. (1989) Comparison of excitatory amino acid-stimulated phosphoinositide hydrolysis and N- `3H:acetylaspartylglutamate binding in rat brain: selective inhibition of phosphoinositide hydrolysis by 2-amino-3phosphonopropionate. J. Neurochem. 53, 273–278.PubMedCrossRefGoogle Scholar
  67. Schoepp, D. D., Johnson, B. G., and Monn, J. A. (1992) Inhibition of cyclic AMP formation by a selective metabotropic glutamate receptor agonist. J. Neurochem. 58, 1184–1186.PubMedCrossRefGoogle Scholar
  68. Schoepp, D. D., Johnson, B. G., True, R. A., and Monn, J. A. (1991) Comparison of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD)- and 1R,3SACPD-stimulated brain phosphoinositide hydrolysis. Eur. J. Pharmacol. Mol. Pharmacol. 207, 351–353.CrossRefGoogle Scholar
  69. Shigemoto, R., Nakanishi, S., and Mizuno, N. (1992) Distribution of the mRNA for a metabotropic glutamate receptor (mGluRl) in the central nervous system: An in situ hybridization study in adult and developing rat. J. Comp. Neurol. 322, 121–135.PubMedCrossRefGoogle Scholar
  70. Sladeczek, F., Pin, J. P., Recasens, M., Bockaert, J., and Weiss, S. (1985) Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 317, 717–719.PubMedCrossRefGoogle Scholar
  71. Stanton, P. K., Chattarji, S., and Sejnowski, T. J. (1991) 2-Amino-3-phosphonopropionic acid, an inhibitor of glutamate-stimulated phosphoinositide turnover, blocks induction of homosynaptic long-term depression, but not potentiation, in rat hippocampus. Neurosci. Lett. 127, 61–66.Google Scholar
  72. Tanabe, Y., Masu, M., Ishii, T., Shigemoto, R., and Nakanishi, S. (1992) A family of metabotropic glutamate receptors. Neuron 8, 169–179.PubMedCrossRefGoogle Scholar
  73. Tanabe, Y., Nomura, A., Masu, M., Shigemoto, R., Mizuno, N., and Nakanishi, S. (1993) Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J. Neurosci. 13, 1372–1378.PubMedGoogle Scholar
  74. Tsubokawa, H., Robinson, H. P. C., Takenawa, T., and Kawai, N. (1993) Block of long-term potentiation by intracellular application of anti-phosphatidylinositol 4,5-bisphosphate antibody in hippocampal pyramidal neurons. Neuroscience 55, 643–651.PubMedCrossRefGoogle Scholar
  75. Vecil, G. G., Li, P. P., and Warsh, J. J. (1992) Evidence for metabotropic excitatory amino acid receptor heterogeneity: Developmental and brain regional studies. J. Neurochem. 59, 252–258.PubMedCrossRefGoogle Scholar
  76. Williams, S. and Johnston, D. (1988) Muscarinic depression of long-term potentiation in CA3 hippocampal neurons. Science 242, 84–87.PubMedCrossRefGoogle Scholar
  77. Yamada, N., Akiyama, K., and Otsuki, S. (1989) Hippocampal kindling enhances excitatory amino acid receptor-mediated polyphosphoinositide hydrolysis in the hippocampus and amygdala/pyriform cortex. Brain Res. 490, 126–132.PubMedCrossRefGoogle Scholar
  78. Zalutsky, R. A. and Nicoll, R. A. (1990) Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248, 1619–1624.PubMedCrossRefGoogle Scholar
  79. Zalutsky, R. A. and Nicoll, R. A. (1992) Mossy fiber long-term potentiation shows specificity but no apparent cooperativity. Neurosci. Lett. 138, 193–197.PubMedCrossRefGoogle Scholar
  80. Zheng, F. and Gallagher, J. P. (1990) Long-term potentiation (LTP) in rat dorsal lateral septal nucleus (DLSN) is not blocked by D,L-2-amino-5-phosphonopentanoate (AP5). Soc. Neurosci. Abstr. 16, 653.Google Scholar
  81. Zheng, F. and Gallagher, J. P. (1992a) Calcium release from internal stores is required for the induction of metabotropic glutamate receptor-dependent long-term potentiation in dorsolateral septal nucleus neurons in vitro. Soc. Neurosci. Abstr. 18, 642.Google Scholar
  82. Zheng, F. and Gallagher, J. P. (1992b) Metabotropic glutamate receptors are required for the induction of long-term potentiation. Neuron 9, 163–172.PubMedCrossRefGoogle Scholar
  83. Zheng, F. and Gallagher, J. P. (1993) Pertussis toxin selectively blocked burst firing induced by 1S,3R-ACPD at rat dorsolateral septal nucleus neurons. Soc. Neurosci. Abstr. 19, 470.Google Scholar
  84. Zheng, F., Lonart, G., Johnson, K. M., and Gallagher, J. P. (1994) (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) induced burst firing via an inositol-1,4,5-triphosphate-independent pathway at rat dorsolateral septal nucleus. Neuropharmacology 33, 97–102.Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Joel P. Gallagher
  • Fang Zheng
  • Patricia Shinnick-Gallagher

There are no affiliations available

Personalised recommendations