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.

  • Letter
  • Published:

Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice

Nature volume 392, pages 601–605 (1998)Cite this article

Abstract

l-glutamate, the neurotransmitter of the majority of excitatory synapses in the brain, acts on three classes of ionotropic receptors: NMDA (N-methyl-d-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. Little is known about the physiological role of kainate receptors because in many experimental situations it is not possible to distinguish them from AMPA receptors1,2. Mice with disrupted kainate receptor genes enable the study of the specific role of kainate receptors in synaptic transmission as well as in the neurotoxic effects of kainate. We have now generated mutant mice lacking the kainate-receptor subunit GluR6. The hippocampal neurons in the CA3 region of these mutant mice are much less sensitive to kainate. In addition, a postsynaptic kainate current evoked in CA3 neurons by a train of stimulation of the mossy fibre system is absent in the mutant3,4. We find that GluR6-deficient mice are less susceptible to systemic administration of kainate, as judged by onset of seizures and by the activation of immediate early genes in the hippocampus. Our results indicate that kainate receptors containing the GluR6 subunit are important in synaptic transmission as well as in the epileptogenic effects of kainate.

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: Disruption of the GluR6 gene by homologous recombination.
Figure 2: Analysis of GluR6 mutant mice by in situ hybridization, immunoblotting and receptor autoradiography.
Figure 3: Reduced sensitivity of CA3 neurons to bath application of kainate in GluR6−/− mice.
Figure 4: Mossy fibre kainate EPSC cannot be detected in GluR6−/− mice.
Figure 5: Analysis of immediate-early gene (IEG) induction and astrogliosis in kainate-treated mice.

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. Lerma, J., Morales, M., Vicente, M. A. & Herreras, O. Glutamate receptors of the kainate type and synaptic transmission. Trends Neurosci. 20, 9–12 (1997).

    Article  CAS  Google Scholar 

  3. 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  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  5. Egebjerg, J., Bettler, B., Hermans-Borgmeyer, I. & Heinemann, S. Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA. Nature 351, 745–748 (1991).

    Article  ADS  CAS  Google Scholar 

  6. Raymond, L. A., Blackstone, C. D. & Huganir, R. L. Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase. Nature 361, 637–641 (1993).

    Article  ADS  CAS  Google Scholar 

  7. Werner, P., Voigt, M., Keinänen, K., Wisden, W. & Seeburg, P. H. Cloning of a putative high-affinity kainate receptor expressed predominantly in hippocampal CA3 cells. Nature 351, 742–744 (1991).

    Article  ADS  CAS  Google Scholar 

  8. Robinson, J. H. & Deadwyler, S. A. Kainic acid produces depolarization of CA3 pyramidal cells in the in vitro hippocampal slices. Brain Res. 221, 117–127 (1981).

    Article  CAS  Google Scholar 

  9. Zucker, R. Short-term synaptic plasticity. Annu. Rev. Neurosci. 12, 13–31 (1989).

    Article  CAS  Google Scholar 

  10. Salin, P., Scanziani, M., Malenka, R. & Nicoll, R. Distinct short-term plasticity at two excitatory synapses in the hippocampus. Proc. Natl Acad. Sci. USA 93, 13304–13309 (1996).

    Article  ADS  CAS  Google Scholar 

  11. Kamiya, H., Shinozaki, H. & Yamamoto, C. Activation of metabotropic glutamate receptor type 2/3 suppresses transmission at rat hippocampal mossy fibre synapse. J. Physiol. 493, 447–455 (1996).

    Article  CAS  Google Scholar 

  12. Ben-Ari, Y. Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14, 375–403 (1985).

    Article  CAS  Google Scholar 

  13. Nadler, J. Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271, 676–677 (1978).

    Article  ADS  CAS  Google Scholar 

  14. Schauwecker, P. & Steward, O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc. Natl Acad. Sci. USA 94, 4103–4108 (1997).

    Article  ADS  CAS  Google Scholar 

  15. Le Gal La Salle, G. Long-lasting and sequential increase in c-fos oncoprotein expression in kainic-acid induced status epilepticus. Neurosci. Lett. 88, 127–130 (1988).

    Article  CAS  Google Scholar 

  16. Smeyne, R. J.et al. Continuous c-fos expression precedes programmed cell death in vivo. Nature 363, 166–169 (1993) (erratum, ibid. 365, 279; (1993).

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  20. Vetter, D. E.et al. Inner ear defects induced by null mutation of the isk gene. Neuron 17, 1251–1264 (1996).

    Article  CAS  Google Scholar 

  21. Bischoff, S., Barhanin, J., Bettler, B., Mulle, C. & Heinemann, S. Spatial distribution of kainate receptor subunit mRNA in the mouse basal ganglia and ventral mesencephalon. J. Comp. Neurol. 379, 541–562 (1997).

    Article  CAS  Google Scholar 

  22. Forrest, D.et al. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron 13, 325–338 (1994).

    Article  CAS  Google Scholar 

  23. Monaghan, D. & Cotman, C. The distribution of [3H]-kainic acid binding sites in rat CNS as determined by autoradiography. Brain Res. 252, 91–100 (1982).

    Article  CAS  Google Scholar 

  24. Young, S., Porrino, L. & Iadarola, M. Cocaine induces striatal c-Fos-immunoreactive proteins via dopaminergic D1 receptors. Proc. Natl Acad. Sci. USA 88, 1291–1295 (1991).

    Article  ADS  CAS  Google Scholar 

  25. Kempermann, G., Kuhn, H. G. & Gage, F. H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. O'Leary, Q.-C. Phan, H. Garjeda, E.Normand and the animal research departments for technical assistance; B. Vissel for help in isolating the genomic clones; M. Iadarola for anti-Fra antibody; M. Allard for help with kainate autoradiography; and Eli Lilly for a gift of GYKI 53655. This work was supported by grants and fellowships from the CNRS, the French MRES, the NIH, the Fondation pour la Recherche Médicale, and the Région Aquitaine (to C.M.), the Schweizerische Nationalfond and the Deutsche Forschungsgemeinschaft (to A.S.), the Spanish MEC (to I.P.-O.), the Conycit-BID (to P.E.C.), a joint program project grant (to F.H.G. and S.F.H.), the NIH (NINDS) and theMcKnight foundation (to S.F.H.).

Author information

Author notes

  1. Bernhard Bettler

    Present address: Novartis AG, 4002, Basel, Switzerland

  2. Christophe Mulle, Andreas Sailer and Jeffrey R. Mann: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Neurobiology Laboratory, La Jolla, 92037, California, USA

    Christophe Mulle, Andreas Sailer, Isabel Pérez-Otaño, Cornelia Maron, Bernhard Bettler & Stephen F. Heinemann

  2. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Heather Dickinson-Anson & Fred H. Gage

  3. Departamento de Fisiologa, Facultad de Medicina, Gral Flores, 2125, Montevideo, Uruguay

    Pablo E. Castillo

  4. Division of Biology, Beckman Research Institute of the City of Hope, Duarte, 91010, California, USA

    Jeffrey R. Mann

  5. UMR CNRS 5541, Université Victor Segalen-Bordeaux 2, Bordeaux, 33076, France

    Christophe Mulle, Pablo E. Castillo & Ingrid Bureau

Authors
  1. Christophe Mulle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Sailer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Pérez-Otaño
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heather Dickinson-Anson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pablo E. Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ingrid Bureau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cornelia Maron
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fred H. Gage
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey R. Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bernhard Bettler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephen F. Heinemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen F. Heinemann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mulle, C., Sailer, A., Pérez-Otaño, I. et al. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392, 601–605 (1998). https://doi.org/10.1038/33408

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/33408

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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