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:

GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells

Abstract

We studied the modulation of GABAergic inhibition by glutamate and kainate acting on GluR5-containing kainate receptors in the CA1 hippocampal region. Glutamate, kainate or ATPA, a selective agonist of GluR5-containing receptors, generates an inward current in inhibitory interneurons and cause repetitive action potential firing. This results in a massive increase of tonic GABAergic inhibition in the somata and apical dendrites of pyramidal neurons. These effects are prevented by the GluR5 antagonist LY 293558. Electrical stimulation of excitatory afferents generates kainate receptor-mediated excitatory postsynaptic currents (EPSCs) and action potentials in identified interneurons that project to the dendrites and somata of pyramidal neurons. Therefore glutamate acting on kainate receptors containing the GluR5 subunit may provide a protective mechanism against hyperexcitability.

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

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

Figure 1: Kainate increases tonic inhibition in CA1 pyramidal neurons.
Figure 2: Activation of kainate receptors containing the GluR5 subunit mediates the kainate-induced increase of tonic inhibition in CA1 pyramidal cells recorded in the presence of GYKI 53655 and D-APV.
Figure 3: Kainate and glutamate applied in the presence of GYKI and D-APV induce high frequency firing in multiple types of interneurons.
Figure 4: The excitatory effects of kainate on interneurons are mediated primarily by GluR5-containing receptors.
Figure 5: Characterization of a GYKI-resistant synaptic response in CA1 interneurons.
Figure 6: Different types of interneurons depolarized by bath application of kainate and filled with biocytin in the CA1 region.
Figure 7: Proposed schemes for the modulation of GABAergic inhibition by kainate in the CA1 region of the hippocampus.

Similar content being viewed by others

References

  1. Siegel, S.J. et al. Distribution of the excitatory amino acid receptor subunits GluR2(4) in monkey hippocampus and colocalization with subunits GluR5-7 and NMDAR1. J. Neurosci. 15, 2707– 2719 (1995).

    Article  CAS  Google Scholar 

  2. Huntley, G.W. et al. Selective distribution of kainate receptor subunit immunoreactivity in monkey neocortex revealed by a monoclonal antibody that recognizes glutamate receptor subunits GluR5/6/7. J. Neurosci. 13, 2965–2981 (1993).

    Article  CAS  Google Scholar 

  3. Good, P.F., Huntley, G.W., Rogers, S.W., Heinemann, S.F. & Morrison, J.H. Organization and quantitative analysis of kainate receptor subunit GluR5-7 immunoreactivity in monkey hippocampus . Brain Res. 624, 347–353 (1993).

    Article  CAS  Google Scholar 

  4. Bahn, S., Volk, B. & Wisden, W. Kainate receptor gene expression in the developing rat brain. J. Neurosci. 14, 5525– 5547 (1994).

    Article  CAS  Google Scholar 

  5. Bettler, B. et al. Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development. Neuron 5, 583–595 (1990).

    Article  CAS  Google Scholar 

  6. 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 

  7. 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 

  8. Nadler, J. Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci. 29, 2031–2042 (1981).

    Article  CAS  Google Scholar 

  9. Ben-Ari, Y. & Gho, M. Long-lasting modification of the synaptic properties of rat CA3 hippocampal neurones induced by kainic acid. J. Physiol. (Lond.) 404, 365–384 (1988).

    Article  CAS  Google Scholar 

  10. Westbrook, G.L. & Lothman, E.W. Cellular and synaptic basis of kainic acid-induced hippocampal epileptiform activity. Brain Res. 273, 97–109 ( 1983).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Gaiarsa, J.L., Beaudoin, M. & Ben-Ari, Y. Effect of neonatal degranulation on the morphological development of rat CA3 pyramidal neurons: Inductive role of mossy fibers on the formation of thorny excrescences. J. Comp. Neurol. 321, 612–625 (1992).

    Article  CAS  Google Scholar 

  13. Gaiarsa, J.-L., Zagrean, L. & Ben-Ari, Y. Neonatal irradiation prevents the formation of hippocampal mossy fibers and the epileptic action of kainate on rat CA3 pyramidal neurons . J. Neurophysiol. 71, 204– 215 (1994).

    Article  CAS  Google Scholar 

  14. Represa, A. & Ben-Ari, Y. Kindling is associated with the formation of novel mossy fibre synapses in the CA3 region. Exp. Brain Res. 92, 69–78 ( 1992).

    Article  CAS  Google Scholar 

  15. Mulle, C. et al. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392, 601–604 (1998).

    Article  CAS  Google Scholar 

  16. 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 

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

    Article  CAS  Google Scholar 

  18. Fisher, R.S. & Alger, B.E. Electrophysiological mechanisms of kainic acid-induced epileptiform activity in the rat hippocampal slice . J. Neurosci. 4, 1312– 1323 (1984).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Freund, T.F. & Buzsáki, G. Interneurons of the hippocampus . Hippocampus 6, 347–470 (1996).

    Article  CAS  Google Scholar 

  22. Rovira, C., Gho, M. & Ben-Ari, Y. Block of GABAB-activated K+ conductance by kainate and quisqualate in rat CA3 hippocampal pyramidal s. Pflugers Arch. 415, 471–478 ( 1990).

    Article  CAS  Google Scholar 

  23. Congar, P., Leinekugel, X., Ben-Ari, Y. & Crepel, V. A long-lasting calcium-activated nonselective cationic current is generated by synaptic stimulation or exogeneous activation of group I metabotropic glutamate receptors in CA1 pyramidal neurons. J. Neurosci. 17 , 5366–5379 (1997).

    Article  CAS  Google Scholar 

  24. Vida, I., Halasy, K., Szinyei, C., Somogyi, P. & Buhl, E.H. Unitary IPSPs evoked by interneurons at the stratum radiatum-stratum lacunosum-moleculare border in the CA1 area of the rat hippocampus in vitro . J. Physiol. (Lond.) 506, 755– 773 (1998).

    Article  CAS  Google Scholar 

  25. Poncer, J.C., Shinozaki, H. & Miles, R. Dual modulation of synaptic inhibition by distinct metabotropic glutamate receptors in the rat hippocampus. J. Physiol. (Lond). 485, 121–134 ( 1995).

    Article  CAS  Google Scholar 

  26. Frazier, C.J. et al. Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J. Neurosci. 18, 1187–1195 (1998).

    Article  CAS  Google Scholar 

  27. Bergles, D.E., Doze, V.A., Madison, D.V. & Smith, S.J. Excitatory actions of norepinephrine on multiple classes of hippocampal CA1 interneurons. J. Neurosci. 16, 572– 585 (1996).

    Article  CAS  Google Scholar 

  28. Kondo, S. & Marty, A. Differential effects of noradrenaline on evoked, spontaneous and miniature IPSCs in rat cerebellar stellate cells . J. Physiol. (Lond.) 509, 233– 243 (1998).

    Article  CAS  Google Scholar 

  29. Radnikow, G. & Misgeld, U. Dopamine D1 receptors facilitate GABAA synaptic currents in the rat substantia nigra pars reticulata. J. Neurosci. 18, 2009–2016 (1998).

    Article  CAS  Google Scholar 

  30. Miller, K.K., Hoffer, A., Svoboda, K.R. & Lupica, C.R. Cholecystokinin increases GABA release by inhibiting a resting K+ conductance in hippocampal interneurons. J. Neurosci. 17, 4994–5003 (1997).

    Article  CAS  Google Scholar 

  31. Wang, H.L., Li, A. & Wu, T. Vasoactive intestinal polypeptide enhances the GABAergic synaptic transmission in cultured hippocampal neurons. Brain Res. 746, 294–300 (1997).

    Article  CAS  Google Scholar 

  32. Batchelor, A.M., Madge, D.J. & Garthwaite, J. Synaptic activation of metabotropic glutamate receptors in the parallel fibre-Purkinje cell pathway in rat cerebellar slices. Neuroscience 63, 911–915 (1994).

    Article  CAS  Google Scholar 

  33. Rodriquez-Moreno, A. & Lerma, J. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20, 1211–1218 ( 1998).

    Article  Google Scholar 

  34. Lerma, J. Kainate reveals its targets. Neuron 19, 1155–1158 (1997).

    Article  CAS  Google Scholar 

  35. Kondo, S. & Marty, A. Synaptic currents at individual connections among stellate cells in rat cerebellar slices. J. Physiol. (Lond.) 509, 221–232 ( 1998).

    Article  CAS  Google Scholar 

  36. Häusser, M. & Clark, B.A. Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration . Neuron 19, 665–678 (1997).

    Article  Google Scholar 

  37. Houser, C.R. & Esclapez, M. Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures . Epilepsy Res. 26, 207– 218 (1996).

    Article  CAS  Google Scholar 

  38. Esclapez, M., Hirsch, J. C., Khazipov, R., Ben-Ari, Y. & Bernard, C. Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy. Proc. Natl. Acad. Sci. USA 94, 12151–12156 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Dinocourt for technical assistance. This work was supported by I.N.S.E.R.M., the French Foundation for Epilepsy Reseach and the Simone and Cino del Duca Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yehezkel Ben-Ari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cossart, R., Esclapez, M., Hirsch, J. et al. GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat Neurosci 1, 470–478 (1998). https://doi.org/10.1038/2185

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/2185

This article is cited by

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