Skip to main content
PMC home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1996 Aug 1;494(Pt 3):743–755. doi: 10.1113/jphysiol.1996.sp021529

Novel glial-neuronal signalling by coactivation of metabotropic glutamate and beta-adrenergic receptors in rat hippocampus.

D G Winder 1, P S Ritch 1, R W Gereau 4th 1, P J Conn 1
PMCID: PMC1160674  PMID: 8865071

Abstract

1. We have previously reported that activation of group II-like metabotropic glutamate receptors (mGluRs) in rat hippocampus results in a potentiation of the accumulation of cAMP elicited by activation of G-protein Gs-coupled receptors. This large increase in cAMP levels results in release of cAMP or a cAMP metabolite and depression of synaptic transmission at the Schaffer collateral-CA1 pyramidal cell synapse through activation of A1 adenosine receptors. 2. Consistent with these studies, we report that antagonists of group II mGluRs block both the potentiation of cAMP accumulation elicited by activation of mGluRs and the depression of synaptic transmission induced by coactivation of mGluRs and beta-adrenergic receptors. 3. In situ hybridization studies suggest that of the cloned group II mGluRs only mGluR-3 mRNA is present in area CA1. Interestingly, mGluR-3 appears to be present predominantly in glia in this region. Thus, we tested the hypothesis that mGluRs coupled to potentiation of cAMP accumulation were present on glia rather than neurons in area CA1. 4. The selective group II mGluR agonist 2S,1'R,2'R,3'R-2(2,3-dicarboxycyclo-propyl)glycine (DCG-IV) failed to enhance cAMP-mediated electrophysiological responses to the beta-adrenergic receptor agonist isoprenaline (Iso) in CA1 pyramidal cells, suggesting that mGluRs coupled to potentiation of cAMP accumulation may not be present in these cells. 5. Pre-incubation of hippocampal slices with either of the selective glial toxins L-alpha-aminoadipic acid (L-AA) or fluorocitrate (FC) blocked mGluR-mediated potentiation of cAMP accumulation. However, L-AA and FC had no discernible effects on viability of CA1 pyramidal cells, or cAMP-mediated electrophysiological effects in these neurons. 6. Pre-incubation of hippocampal slices with the neurotoxin kainate resulted in disruption of neuronal transmission and degeneration of neurons in area CA1, but had no effect on mGluR-mediated potentiation of cAMP accumulation. 7. Pre-incubation of hippocampal slices with the cAMP/cAMP metabolite transport blocker probenicid blocked the depression of synaptic transmission elicited by coapplication of Iso and DCG-IV, while having no significant effect on cAMP accumulation elicited by these agonists. 8. Taken together, these data suggest that mGluRs coupled to potentiation of cAMP accumulation are present on glia rather than neurons in area CA1 of hippocampus. This suggests that a novel form of glial-neuronal communication may exist, since activation of these mGluRs in concert with beta-adrenergic receptors results in depression of synaptic transmission.

Full text

PDF
743

Images in this article

750Figure 5
on p.750
751Figure 6
on p.751

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andrade R. Enhancement of beta-adrenergic responses by Gi-linked receptors in rat hippocampus. Neuron. 1993 Jan;10(1):83–88. doi: 10.1016/0896-6273(93)90244-l. [DOI] [PubMed] [Google Scholar]
  2. Anholt R. R. Signal integration in the nervous system: adenylate cyclases as molecular coincidence detectors. Trends Neurosci. 1994 Jan;17(1):37–41. doi: 10.1016/0166-2236(94)90033-7. [DOI] [PubMed] [Google Scholar]
  3. Aoki C. Beta-adrenergic receptors: astrocytic localization in the adult visual cortex and their relation to catecholamine axon terminals as revealed by electron microscopic immunocytochemistry. J Neurosci. 1992 Mar;12(3):781–792. doi: 10.1523/JNEUROSCI.12-03-00781.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berg-Johnsen J., Paulsen R. E., Fonnum F., Langmoen I. A. Changes in evoked potentials and amino acid content during fluorocitrate action studied in rat hippocampal cortex. Exp Brain Res. 1993;96(2):241–246. doi: 10.1007/BF00227104. [DOI] [PubMed] [Google Scholar]
  5. Casabona G., Genazzani A. A., Di Stefano M., Sortino M. A., Nicoletti F. Developmental changes in the modulation of cyclic AMP formation by the metabotropic glutamate receptor agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid in brain slices. J Neurochem. 1992 Sep;59(3):1161–1163. doi: 10.1111/j.1471-4159.1992.tb08360.x. [DOI] [PubMed] [Google Scholar]
  6. Desai M. A., Smith T. S., Conn P. J. Multiple metabotropic glutamate receptors regulate hippocampal function. Synapse. 1992 Nov;12(3):206–213. doi: 10.1002/syn.890120305. [DOI] [PubMed] [Google Scholar]
  7. Dunwiddie T. V., Hoffer B. J. Adenine nucleotides and synaptic transmission in the in vitro rat hippocampus. Br J Pharmacol. 1980 May;69(1):59–68. doi: 10.1111/j.1476-5381.1980.tb10883.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dunwiddie T. V., Taylor M., Heginbotham L. R., Proctor W. R. Long-term increases in excitability in the CA1 region of rat hippocampus induced by beta-adrenergic stimulation: possible mediation by cAMP. J Neurosci. 1992 Feb;12(2):506–517. doi: 10.1523/JNEUROSCI.12-02-00506.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Garthwaite J., Wilkin G. P. Kainic acid receptors and neurotoxicity in adult and immature rat cerebellar slices. Neuroscience. 1982 Oct;7(10):2499–2514. doi: 10.1016/0306-4522(82)90210-x. [DOI] [PubMed] [Google Scholar]
  10. Genazzani A. A., Casabona G., L'Episcopo M. R., Condorelli D. F., Dell'Albani P., Shinozaki H., Nicoletti F. Characterization of metabotropic glutamate receptors negatively linked to adenylyl cyclase in brain slices. Brain Res. 1993 Sep 17;622(1-2):132–138. doi: 10.1016/0006-8993(93)90811-z. [DOI] [PubMed] [Google Scholar]
  11. Gereau R. W., 4th, Conn P. J. A cyclic AMP-dependent form of associative synaptic plasticity induced by coactivation of beta-adrenergic receptors and metabotropic glutamate receptors in rat hippocampus. J Neurosci. 1994 May;14(5 Pt 2):3310–3318. doi: 10.1523/JNEUROSCI.14-05-03310.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gereau R. W., 4th, Conn P. J. Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1. J Neurosci. 1995 Oct;15(10):6879–6889. doi: 10.1523/JNEUROSCI.15-10-06879.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gereau R. W., 4th, Conn P. J. Potentiation of cAMP responses by metabotropic glutamate receptors depresses excitatory synaptic transmission by a kinase-independent mechanism. Neuron. 1994 May;12(5):1121–1129. doi: 10.1016/0896-6273(94)90319-0. [DOI] [PubMed] [Google Scholar]
  14. Gereau R. W., 4th, Conn P. J. Presynaptic enhancement of excitatory synaptic transmission by beta-adrenergic receptor activation. J Neurophysiol. 1994 Sep;72(3):1438–1442. doi: 10.1152/jn.1994.72.3.1438. [DOI] [PubMed] [Google Scholar]
  15. Gereau R. W., 4th, Conn P. J. Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability. J Neurophysiol. 1995 Jul;74(1):122–129. doi: 10.1152/jn.1995.74.1.122. [DOI] [PubMed] [Google Scholar]
  16. Gereau R. W., 4th, Winder D. G., Conn P. J. Pharmacological differentiation of the effects of co-activation of beta-adrenergic and metabotropic glutamate receptors in rat hippocampus. Neurosci Lett. 1995 Feb 17;186(2-3):119–122. doi: 10.1016/0304-3940(95)11300-l. [DOI] [PubMed] [Google Scholar]
  17. Hansson E., Rönnbäck L. Astrocytes in glutamate neurotransmission. FASEB J. 1995 Mar;9(5):343–350. doi: 10.1096/fasebj.9.5.7534736. [DOI] [PubMed] [Google Scholar]
  18. Heginbotham L. R., Dunwiddie T. V. Long-term increases in the evoked population spike in the CA1 region of rat hippocampus induced by beta-adrenergic receptor activation. J Neurosci. 1991 Aug;11(8):2519–2527. doi: 10.1523/JNEUROSCI.11-08-02519.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Huck S., Grass F., Hörtnagl H. The glutamate analogue alpha-aminoadipic acid is taken up by astrocytes before exerting its gliotoxic effect in vitro. J Neurosci. 1984 Oct;4(10):2650–2657. doi: 10.1523/JNEUROSCI.04-10-02650.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jane D. E., Jones P. L., Pook P. C., Tse H. W., Watkins J. C. Actions of two new antagonists showing selectivity for different sub-types of metabotropic glutamate receptor in the neonatal rat spinal cord. Br J Pharmacol. 1994 Jul;112(3):809–816. doi: 10.1111/j.1476-5381.1994.tb13151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Karbon E. W., Duman R. S., Enna S. J. GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex. Brain Res. 1984 Jul 23;306(1-2):327–332. doi: 10.1016/0006-8993(84)90382-2. [DOI] [PubMed] [Google Scholar]
  22. Knöpfel T., Lukic S., Leonard T., Flor P. J., Kuhn R., Gasparini F. Pharmacological characterization of MCCG and MAP4 at the mGluR1b, mGluR2 and mGluR4a human metabotropic glutamate receptor subtypes. Neuropharmacology. 1995 Aug;34(8):1099–1102. doi: 10.1016/0028-3908(95)00111-i. [DOI] [PubMed] [Google Scholar]
  23. Madison D. V., Nicoll R. A. Cyclic adenosine 3',5'-monophosphate mediates beta-receptor actions of noradrenaline in rat hippocampal pyramidal cells. J Physiol. 1986 Mar;372:245–259. doi: 10.1113/jphysiol.1986.sp016007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Newberry N. R., Nicoll R. A. Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. 1984 Mar 29-Apr 4Nature. 308(5958):450–452. doi: 10.1038/308450a0. [DOI] [PubMed] [Google Scholar]
  25. Paulsen R. E., Contestabile A., Villani L., Fonnum F. An in vivo model for studying function of brain tissue temporarily devoid of glial cell metabolism: the use of fluorocitrate. J Neurochem. 1987 May;48(5):1377–1385. doi: 10.1111/j.1471-4159.1987.tb05674.x. [DOI] [PubMed] [Google Scholar]
  26. Peakman M. C., Hill S. J. Adenosine A2B-receptor-mediated cyclic AMP accumulation in primary rat astrocytes. Br J Pharmacol. 1994 Jan;111(1):191–198. doi: 10.1111/j.1476-5381.1994.tb14043.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pin J. P., Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995 Jan;34(1):1–26. doi: 10.1016/0028-3908(94)00129-g. [DOI] [PubMed] [Google Scholar]
  28. Rosenberg P. A., Knowles R., Knowles K. P., Li Y. Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture. J Neurosci. 1994 May;14(5 Pt 2):2953–2965. doi: 10.1523/JNEUROSCI.14-05-02953.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schoepp D. D., Johnson B. G. Metabotropic glutamate receptor modulation of cAMP accumulation in the neonatal rat hippocampus. Neuropharmacology. 1993 Dec;32(12):1359–1365. doi: 10.1016/0028-3908(93)90031-w. [DOI] [PubMed] [Google Scholar]
  30. Schwartz E. A. L-glutamate conditionally modulates the K+ current of Müller glial cells. Neuron. 1993 Jun;10(6):1141–1149. doi: 10.1016/0896-6273(93)90062-v. [DOI] [PubMed] [Google Scholar]
  31. Stone E. A., Sessler F. M., Liu W. M. Glial localization of adenylate-cyclase-coupled beta-adrenoceptors in rat forebrain slices. Brain Res. 1990 Oct 22;530(2):295–300. doi: 10.1016/0006-8993(90)91298-u. [DOI] [PubMed] [Google Scholar]
  32. Vignes M., Clarke V. R., Davies C. H., Chambers A., Jane D. E., Watkins J. C., Collingridge G. L. Pharmacological evidence for an involvement of group II and group III mGluRs in the presynaptic regulation of excitatory synaptic responses in the CA1 region of rat hippocampal slices. Neuropharmacology. 1995 Aug;34(8):973–982. doi: 10.1016/0028-3908(95)00093-l. [DOI] [PubMed] [Google Scholar]
  33. Wang J., Johnson K. M. Regulation of striatal cyclic-3',5'-adenosine monophosphate accumulation and GABA release by glutamate metabotropic and dopamine D1 receptors. J Pharmacol Exp Ther. 1995 Nov;275(2):877–884. [PubMed] [Google Scholar]
  34. Winder D. G., Conn P. J. Activation of metabotropic glutamate receptors in the hippocampus increases cyclic AMP accumulation. J Neurochem. 1992 Jul;59(1):375–378. doi: 10.1111/j.1471-4159.1992.tb08914.x. [DOI] [PubMed] [Google Scholar]
  35. Winder D. G., Conn P. J. Activation of metabotropic glutamate receptors increases cAMP accumulation in hippocampus by potentiating responses to endogenous adenosine. J Neurosci. 1993 Jan;13(1):38–44. doi: 10.1523/JNEUROSCI.13-01-00038.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Winder D. G., Conn P. J. Metabotropic glutamate receptor (mGluR)-mediated potentiation of cyclic AMP responses does not require phosphoinositide hydrolysis: mediation by a group II-like mGluR. J Neurochem. 1995 Feb;64(2):592–599. doi: 10.1046/j.1471-4159.1995.64020592.x. [DOI] [PubMed] [Google Scholar]
  37. Winder D. G., Smith T., Conn P. J. Pharmacological differentiation of metabotropic glutamate receptors coupled to potentiation of cyclic adenosine monophosphate responses and phosphoinositide hydrolysis. J Pharmacol Exp Ther. 1993 Aug;266(2):518–525. [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES