Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures

Nature Neuroscience volume 5, pages 796–804 (2002)Cite this article

Abstract

Developments in the molecular biology and pharmacology of GLUK5, a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLUK5-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLUK5-containing kainate receptors prevented development of epileptiform activity—evoked by the muscarinic agonist, pilocarpine—and inhibited the activity when it was pre-established. In conscious rats, these GLUK5 antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLUK5 antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLUK5 kainate receptor antagonists offer a potential new therapy for epilepsy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Antagonism of GLUK5-containing kainate receptors suppresses kainate-induced disinhibition in the hippocampus.
Figure 2: GLUK5 antagonists and pilocarpine-induced epileptiform activity.
Figure 3: The induction of epileptiform activity requires activation of kainate but not AMPA receptors.
Figure 4: LY377770 is able to block established pilocarpine-induced limbic seizures.
Figure 5: GLUK5 receptor antagonists prevent focally evoked pilocarpine-induced limbic seizures and accompanying rises in extracellular (EC) glutamate and GABA concentrations in conscious rats.
Figure 6: LY377770 (30 mg/kg) prevents the initiation of pilocarpine-induced seizures in conscious rats.
Figure 7: GLUK5 receptor antagonists inhibit the generation of electrically induced but not picrotoxin-induced epileptiform activity.

Similar content being viewed by others

References

  1. Bettler, B. & Mulle, C. AMPA and kainate receptors. Neuropharmacology 34, 123–139 (1995).

    Article  CAS  Google Scholar 

  2. Bleakman, D. & Lodge, D. Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37, 1187–1204 (1998).

    Article  CAS  Google Scholar 

  3. Nadler, J.V., Perry, B.W. & Cotman, C.W. Intraventricular kainic acid preferentially destroys hippocampal cells. Nature, 271, 676–677 (1978).

    Article  CAS  Google Scholar 

  4. Ben-Ari, Y., Tremblay, E., Ottersen, O.P. & Meldrum, B.S. The role of epileptic activity in hippocampal and 'remote' cerebral lesions induced by kainic acid. Brain Res. 191, 79–97 (1980).

    Article  CAS  Google Scholar 

  5. Ashwood, T.J., Lancaster, B. & Wheal, H.V. Intracellular electrophysiology of CA1 pyramidal neurones in slices of the kainic acid lesioned hippocampus of the rat. Exp. Brain Res. 62, 189–198 (1986).

    Article  CAS  Google Scholar 

  6. Chittajallu, R. et al. Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. Nature 379, 78–81 (1996).

    Article  CAS  Google Scholar 

  7. Vignes, M. & Collingridge, G.L. The synaptic activation of kainate receptors. Nature 388, 179–182 (1997).

    Article  CAS  Google Scholar 

  8. Vignes, M., Bleakman, D., Lodge, D. & Collingridge, G.L. The synaptic activation of the GluR5 subtype of kainate receptor in area CA3 of the rat hippocampus. Neuropharmacology 36, 1477–1481 (1997).

    Article  CAS  Google Scholar 

  9. Castillo, P.E., Malenka, R.C. & Nicoll, R.A. Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388, 182–186 (1997).

    Article  CAS  Google Scholar 

  10. Clarke, V.R.J. et al. A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389, 599–603 (1997).

    Article  CAS  Google Scholar 

  11. Rodriguez-Moreno, A., Herrerras, O. & Lerma, J. Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus. Neuron 19, 893–901 (1997).

    Article  CAS  Google Scholar 

  12. O'Neill, M.J. et al. Decahydroisoquinolines: novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia. Neuropharmacology 37, 1211–1222 (1998).

    Article  CAS  Google Scholar 

  13. Li, H. & Rogawski, M.A. GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro. Neuropharmacology 37, 1279–1286 (1998).

    Article  CAS  Google Scholar 

  14. Cossart, R. et al. GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat. Neurosci. 1, 470–478 (1998).

    Article  CAS  Google Scholar 

  15. Frerking, M., Malenka, R.C. & Nicoll, R.A. Synaptic activation of kainate receptors on hippocampal interneurons. Nat. Neurosci. 1, 479–486 (1998).

    Article  CAS  Google Scholar 

  16. Vignes, M. et al. The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus. Neuropharmacology 37, 1269–1277 (1998).

    Article  CAS  Google Scholar 

  17. Mulle, C. et al. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392, 601–605 (1998).

    Article  CAS  Google Scholar 

  18. Chittajallu, R., Braithwaite S.P., Clarke, V.R.J. & Henley, J.M. Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol. Sci. 20, 26–35 (1999).

    Article  CAS  Google Scholar 

  19. Bortolotto, Z.A. et al. Kainate receptors are involved in synaptic plasticity. Nature 402, 297–301 (1999).

    Article  CAS  Google Scholar 

  20. Min, M.Y., Melyan, Z. & Kullmann, D.M. Synaptically released glutamate reduces γ-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proc. Natl. Acad. Sci. USA 96, 9932–9937 (1999).

    Article  CAS  Google Scholar 

  21. Frerking, M., Petersen, C.C. & Nicoll, R.A. Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus. Proc. Natl. Acad. Sci. USA 96, 12917–12922 (1999).

    Article  CAS  Google Scholar 

  22. O'Neill, M.J. et al. LY377770, a novel iGluR5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia. Neuropharmacology 39, 1575–1588 (2000).

    Article  CAS  Google Scholar 

  23. Rodriguez-Moreno, A., Lopez-Garcia, J.C. & Lerma, J. Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons. Proc. Natl. Acad. Sci. USA 97, 1293–1298 (2000).

    Article  CAS  Google Scholar 

  24. Paternain, A.V., Herrera, M.T., Nieto, M.A. & Lerma, J. GLUR5 and GLUR6 receptor subunits coexist in hippocampal neurons and coassemble to form functional receptors. J. Neurosci. 20, 196–205 (2000).

    Article  CAS  Google Scholar 

  25. Li, H., Chen, A., Xing, G., Wei, M.L. & Rogawski, M.A. Kainate receptor-mediated heterosynaptic facilitation in the amygdala. Nat. Neurosci. 4, 612–620 (2001).

    Article  CAS  Google Scholar 

  26. Huettner, J.E. Kainate receptors: knocking out plasticity. Trends Neurosci. 24, 365–366 (2001).

    Article  CAS  Google Scholar 

  27. Schmitz, D., Mellor, J. & Nicoll, R.A. Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291, 1972–1975 (2001).

    Article  CAS  Google Scholar 

  28. Contractor, A., Swanson, G. & Heinemann, S.F. Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus. Neuron 29, 209–216 (2001).

    Article  CAS  Google Scholar 

  29. Wilding, T.J. & Huettner, J.E. Functional diversity and developmental changes in rat neuronal kainate receptors. J. Physiol. 532.2, 411–421 (2001).

    Article  Google Scholar 

  30. Lauri, S.E. et al. A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP. Neuron 32, 697–709 (2001).

    Article  CAS  Google Scholar 

  31. Bleakman, D. et al. Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydro-isoquinoline-3 carboxylic acid. Mol. Pharmacol. 49, 581–585 (1996).

    CAS  PubMed  Google Scholar 

  32. Lodge, D. & Dingledine, R. in The IUPHAR Compendium of Receptor Characterization and Classification 2nd edn. 189–194 (IUPHAR Media, London, 2000).

    Google Scholar 

  33. Kehl, S.J., McLennan, H. & Collingridge, G.L. Effects of folic and kainic acids on synaptic responses of hippocampal neurones. Neuroscience 11, 111–124 (1984).

    Article  CAS  Google Scholar 

  34. Turski, L., Ikonomidou, C., Turski, W.A., Bortolotto, Z.A. & Cavalheiro, E.A. Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3, 154–171 (1989).

    Article  CAS  Google Scholar 

  35. Smolders, I., Khan, G.M., Manil, J., Ebinger, G. & Michotte, Y. NMDA receptor-mediated pilocarpine-induced seizures: characterization in freely moving rats using microdialysis. Br. J. Pharmacol. 121, 1171–1179 (1997).

    Article  CAS  Google Scholar 

  36. Rutecki, P.A. & Yang, Y. Ictal epileptiform activity in the CA3 region of hippocampal slices produced by pilocarpine. J. Neurophysiol. 79, 3019–3029 (1998).

    Article  CAS  Google Scholar 

  37. Rogawski, M.A., Kurzman, P.S., Yamaguchi, S.I. & Li, H. Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse. Neuropharmacology, 40, 28–35 (2001).

    Article  CAS  Google Scholar 

  38. De Sarro, G. et al. Anticonvulsant activity and plasma level of 2,3-benzodiazepin-4-ones (CFMs) in genetically epilepsy-prone rats. Pharmacol. Biochem. Behav. 63, 621–627 (1999).

    Article  CAS  Google Scholar 

  39. Paternain, A.V., Morales, M. & Lerma, J. Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons. Neuron 14, 185–189 (1995).

    Article  CAS  Google Scholar 

  40. Wilding, T.J. & Huettner, J.E. Differential antagonism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-preferring and kainate-preferring receptors by 2,3-benzodiazepines. Mol. Pharmacol. 47, 582–587 (1995).

    CAS  PubMed  Google Scholar 

  41. Stasheff, S.F., Bragdon, A.C. & Wilson, W.A. Induction of epileptiform activity in hippocampal slices by trains of electrical stimuli. Brain Res. 344, 296–302 (1985).

    Article  CAS  Google Scholar 

  42. Krnjevic, K. in GABA Mechanisms in Epilepsy 47–87 (Wiley-Liss, New York, 1991).

    Google Scholar 

  43. Matagne, A. & Klitgaard, H. Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res. 31, 59–71 (1998).

    Article  CAS  Google Scholar 

  44. Lauri, S.E. et al. Synaptic activation of a presynaptic kainate receptor facilitates AMPA receptor-mediated synaptic transmission at hippocampal mossy fibre synapses. Neuropharmacology 41, 907–915 (2001).

    Article  CAS  Google Scholar 

  45. Mattson, R.H. Efficacy and adverse effects of established and new antiepileptic drugs. Epilepsia 36 suppl. 2, S13–S26 (1995).

    Article  CAS  Google Scholar 

  46. Rogvi-Hansen, B. & Gram, L. Adverse effects of established and new antiepileptic drugs: an attempted comparison. Pharmacol. Ther. 68, 425–434 (1995).

    Article  CAS  Google Scholar 

  47. Curry, W.J. & Kulling, D.L. Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin. Am. Fam. Physician 57, 513–524 (1998).

    CAS  PubMed  Google Scholar 

  48. Sander, T. et al. Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism. Am. J. Med. Genet. 74, 416–421 (1997).

    Article  CAS  Google Scholar 

  49. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates 2nd edn. (Academic, San Diego, 1986).

    Google Scholar 

  50. Smolders, I., Sarre, S., Michotte, Y. & Ebinger, G. The analysis of excitatory, inhibitory and other amino acids in rat brain microdialysates using microbore liquid chromatography. J. Neurosci. Meth. 57, 47–53 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I. Smolders is a postdoctoral fellow of the FWO-Vlaanderen, Belgium. We thank C. Felder of Eli Lilly & Co. for help in profiling LY382884 and LY377770 in vitro and S. White and H. Wolf for help with the 6-Hz studies. We thank R. Berckmans, G. De Smet and C. De Rijck for technical assistance. Supported by the MRC, Wellcome Trust, FWO-Vlaanderen, VUB & the Koningin Elisabeth Stichting.

Author information

Author notes

  1. Ilse Smolders and Zuner A. Bortolotto: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry & Drug Analysis, Pharmaceutical Institute, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels, 1090, Belgium

    Ilse Smolders, Ghous M. Khan & Yvette Michotte

  2. Department of Anatomy, MRC Centre for Synaptic Plasticity, Medical School, University of Bristol, Bristol, BS8 1TD, UK

    Zuner A. Bortolotto, Vernon R. J. Clarke, Ruth Warre & Graham L. Collingridge

  3. Eli Lilly & Co., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK

    Michael J. O'Neill & David Lodge

  4. Eli Lilly & Co., Lilly Corporate Centre, Indianapolis, 46285-0814, Indiana, USA

    Paul L. Ornstein, David Bleakman, AnnMarie Ogden & Brianne Weiss

  5. Epilepsy Branch, NINDS, NIH, 7550 Wisconsin Ave, Bethesda, 20892, Maryland, USA

    James P. Stables

  6. Allelix Pharmaceuticals, 6850 Goreway Drive, Mississauga, L4V 1V7, Ontario, Canada

    Ken H. Ho

  7. Department of Neurology, University Hospital AZ-VUB, Laarbeeklaan 101, Brussels, 1090, Belgium

    Guy Ebinger

Authors
  1. Ilse Smolders
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zuner A. Bortolotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vernon R. J. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruth Warre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ghous M. Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael J. O'Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul L. Ornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Bleakman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. AnnMarie Ogden
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Brianne Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James P. Stables
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ken H. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Guy Ebinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Graham L. Collingridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. David Lodge
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yvette Michotte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Lodge.

Ethics declarations

Competing interests

Of the authors, Michael J. O'Neill, Paul L. Ornstein, David Bleakman, AnnMarie Ogden, Brianne Weiss, Ken H. Ho and David Lodge are employed by Eli Lilly & Co. Ltd. Ken H. Ho, worked for Allelix Biopharmaceuticals at the time some of these data were collected and Allelix Biopharmaceuticals had a collaborative financial agreement at that time.

Other than this, none of the authors or their institutions received any payment, financial support or other remuneration for this work from Eli Lilly & Co. Ltd, other than that the three compounds LY382884, LY377770 and GYKI53655 were provided free of charge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smolders, I., Bortolotto, Z., Clarke, V. et al. Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures. Nat Neurosci 5, 796–804 (2002). https://doi.org/10.1038/nn880

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn880

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing