Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability | Nature Medicine
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:

Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability

Nature Medicine volume 7, pages 331–337 (2001)Cite this article

Abstract

Febrile seizures are the most common type of developmental seizures, affecting up to 5% of children. Experimental complex febrile seizures involving the immature rat hippocampus led to a persistent lowering of seizure threshold despite an upregulation of inhibition. Here we provide a mechanistic resolution to this paradox by showing that, in the hippocampus of rats that had febrile seizures, the long-lasting enhancement of the widely expressed intrinsic membrane conductance Ih converts the potentiated synaptic inhibition to hyperexcitability in a frequency-dependent manner. The altered gain of this molecular inhibition–excitation converter reveals a new mechanism for controlling the balance of excitation–inhibition in the limbic system. In addition, here we show for the first time that h-channels are modified in a human neurological disease paradigm.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Long-lasting shift in h-current activation following hyperthermia-induced seizures.
Figure 2: Kinetic changes in Ih following seizures and the effect of modulation of intracellular cAMP.
Figure 3: Enhanced activation of altered Ih by hyperpolarizing inputs and post-inhibitory rebound firing following hyperthermia-induced seizures.
Figure 4: Mechanism of post-inhibitory rebound firing, specificity of the changes affecting Ih, and pattern of spontaneous GABA-receptor activation after febrile seizures.
Figure 5: Multicompartmental modeling shows importance of altered h-channels in limiting inhibitory inputs and generating post-inhibitory rebound firing.

Similar content being viewed by others

References

  1. Otis, T.S., De Koninck, Y. & Mody, I. Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc. Natl. Acad. Sci. USA 91, 7698–702 (1994).

    Article  CAS  Google Scholar 

  2. Nusser, Z., Hájos, N., Somogyi, P. & Mody, I. Increased number of synaptic GABA(A) receptors underlies potentiation at hippocampal inhibitory synapses. Nature 395, 172–177 (1998).

    Article  CAS  Google Scholar 

  3. Brooks-Kayal, A.R., Shumate, M.D., Jin, H., Rikhter, T.Y. & Coulter, D.A. Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy. Nature Med. 4, 1166–1172 (1998).

    Article  CAS  Google Scholar 

  4. Buhl, E.H., Otis, T.S. & Mody, I. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science 271, 369–373 (1996).

    Article  CAS  Google Scholar 

  5. Chen, K., Baram, T.Z. & Soltesz, I. Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits. Nature Med. 5, 888–894 (1999).

    Article  CAS  Google Scholar 

  6. Walker, M.C. & Kullmann, D.M. Febrile convulsions: a 'benign' condition? Nature Med. 5, 871–872 (1999).

    Article  CAS  Google Scholar 

  7. Shinnar, S. Prolonged febrile seizures and mesial temporal sclerosis. Ann. Neurol. 43, 411–412 (1998).

    Article  CAS  Google Scholar 

  8. Cendes, F. et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study. Neurology 43, 1083–1087 (1993).

    Article  CAS  Google Scholar 

  9. Dube, C. et al. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann. Neurol. 47, 336–344 (2000).

    Article  CAS  Google Scholar 

  10. Baram, T.Z., Gerth, A. & Schultz, L. Febrile seizures: an appropriate-aged model suitable for long-term studies. Dev. Brain Res. 98, 265–270 (1997).

    Article  CAS  Google Scholar 

  11. VanLandingham, K.E., Heinz, E.R., Cavazos, J.E. & Lewis, D.V. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann. Neurol. 43, 413–426 (1998).

    Article  CAS  Google Scholar 

  12. Brown, H.F., DiFrancesco, D. & Noble, S.J. How does adrenaline accelerate the heart? Nature 280, 235–236 (1979).

    Article  CAS  Google Scholar 

  13. Mayer, M.L. & Westbrook, G.L. A voltage-clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurones. J. Physiol. (Lond.) 340, 19–45 (1983).

    Article  CAS  Google Scholar 

  14. Pape, H.C. & McCormick, D.A. Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. Nature 340, 715–718 (1989).

    Article  CAS  Google Scholar 

  15. Soltesz, I. et al. Two inward currents and the transformation of low-frequency oscillations of thalamocortical cells. J. Physiol. (Lond.) 441, 175–197 (1991).

    Article  CAS  Google Scholar 

  16. Maccaferri, G. & McBain, C.J. The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriens-alveus interneurones. J. Physiol. (Lond.) 497, 119–130 (1996).

    Article  CAS  Google Scholar 

  17. Pape, H.C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Ann. Rev. Physiol. 58, 299–327 (1996).

    Article  CAS  Google Scholar 

  18. Santoro, B. & Tibbs, G.R. The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann. NY Acad. Sci. 868, 741–764 (1999).

    Article  CAS  Google Scholar 

  19. Beaumont, V. & Zucker, R.S. Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. Nature Neurosci. 3, 133–141 (2000).

    Article  CAS  Google Scholar 

  20. Siegelbaum, S.A. Presynaptic facilitation by hyperpolarization-activated pacemaker channels. Nature Neurosci. 3, 101–102 (2000).

    Article  CAS  Google Scholar 

  21. BoSmith, R.E., Briggs, I. & Sturgess, N.C. Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Brit. J. Pharm. 110, 343–349 (1993).

    Article  CAS  Google Scholar 

  22. Soltesz, I. & Deschênes, M. Low- and high-frequency membrane-potential oscillations during theta activity in morphologically identified neurons of the rat hippocampus during ketamine-xylazine anesthesia. J. Neurophysiol. 70, 97–116 (1993).

    Article  CAS  Google Scholar 

  23. Harris, N.C & Constanti, A. Mechanism of block by ZD-7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro. J. Neurophysiol. 74, 2366–2378 (1995).

    Article  CAS  Google Scholar 

  24. Staley, K.J., Soldo, B.L. & Proctor, W.R. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 269, 977–981 (1995).

    Article  CAS  Google Scholar 

  25. Storm, J.F. Temporal integration by a slowly inactivating K+ current in hippocampal neurons. Nature 336, 379–381 (1988).

    Article  CAS  Google Scholar 

  26. Krause, M. & Pedarzani, P. A protein phosphatase is involved in the cholinergic suppression of the Ca2+-activated K+ current sIAHP in hippocampal pyramidal neurons. Neuropharmacology 39, 1274–1283 (2000).

    Article  CAS  Google Scholar 

  27. Hines, M.L. Computer modeling methods for neurons. in The Handbook of Brain Theory and Neural Networks. (ed. Arbib, M.A.) 226–230 (MIT Press, Cambridge, Massachusetts, 1995).

    Google Scholar 

  28. Aradi, I. & Holmes, W.R. Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability. J. Comput. Neurosci. 6, 215–235 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci. 18, 7613–7624 (1998).

    Article  CAS  Google Scholar 

  31. Holmes, G.L. & Ben-Ari, Y. Seizures in the developing brain: Perhaps not so benign after all. Neuron 21, 1231–1234 (1998).

    Article  CAS  Google Scholar 

  32. Villeneuve, N., Ben-Ari, Y., Holmes, G.L. & Gaiarsa, J.-L. Neonatal seizures induced persistent changes in intrinsic properties of CA1 rat hippocampal cells. Ann. Neurol. 47, 729–738 (2000).

    Article  CAS  Google Scholar 

  33. Santoro, B., Grant, S.G., Bartsch, D. & Kandel, E.R. Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA 94, 14815–14820 (1997).

    Article  CAS  Google Scholar 

  34. Santoro, B. et al. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93, 717–729 (1998).

    Article  CAS  Google Scholar 

  35. Ludwig, A., Zong, X., Jeglitsch, M., Hofmann, F. & Biel, M. A family of hyperpolarization-activated mammalian cation channels. Nature 393, 587–591 (1998).

    Article  CAS  Google Scholar 

  36. Moosmang, S., Biel, M., Hofmann, F. & Ludwig, A. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem . 380, 975–980 (1999).

    Article  CAS  Google Scholar 

  37. Maccaferri, G., Mangoni, M., Lazzari, A. & DiFrancesco, D. Properties of the hyperpolarization-activated current in rat hippocampal CA1 pyramidal cells. J. Neurophysiol. 69, 2129–2136 (1993).

    Article  CAS  Google Scholar 

  38. Lüthi, A. & McCormick, D.A. Modulation of a pacemaker current through Ca2+-induced stimulation of cAMP production. Nature Neurosci. 2, 634–41 (1999).

    Article  Google Scholar 

  39. DiFrancesco, D. & Tortora, P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351, 145–7 (1991).

    Article  CAS  Google Scholar 

  40. Baker, K., Warren, K.S. Yellen, G., & Fishman, M.C. Defective “pacemaker” current (Ih) in a zebrafish mutant with a slow heart rate. Proc. Natl. Acad. Sci. USA 94, 4554–4559 (1997).

    Article  CAS  Google Scholar 

  41. Smith, R.L., Clayton, G.H., Wilcox, C.L., Escudero, K.W. & Staley, K.J. Differential expression of an inwardly rectifying chloride conductance in rat brain neurons: A potential mechanism for cell-specific modulation of inhibition. J. Neurosci. 15, 4057–4067 (1995).

    Article  CAS  Google Scholar 

  42. Hollrigel, G.H., Toth, K. & Soltesz, I. Neuroprotection by propofol in acute mechanical injury: Role of GABAergic inhibition. J. Neurophysiol. 76, 2412–2422 (1996).

    Article  CAS  Google Scholar 

  43. Spruston, N. & Johnston, D. Perforated patch-clamp analysis of the passive membrane properties of three classes of hippocampal neurons. J. Neurophysiol. 67, 508–529 (1992).

    Article  CAS  Google Scholar 

  44. Numann, R.E., Wadman, W.J. & Wong, R.K. Outward currents of single hippocampal cells obtained from the adult guinea-pig. J. Physiol. (Lond.) 393, 331–353 (1987).

    Article  CAS  Google Scholar 

  45. Magee, J.C. & Johnston, D. Characterization of single voltage-gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J. Physiol. (Lond.) 487, 67–90 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Zhu for technical assistance. This work was financially supported by the NIH (NS38580 to I.S. and NS35439 to T.Z.B.), by the UC Systemwide Biotechnology Research and Education Program (BREP-98-02 to T.Z.B. & I.S.) and by a Postdoctoral Fellowship from the Epilepsy Foundation of America (to I.A.).

Author information

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, California, USA

    Kang Chen, Ildiko Aradi, Niklas Thon, Mariam Eghbal-Ahmadi, Tallie Z. Baram & Ivan Soltesz

  2. Department of Pediatrics, University of California at Irvine, Irvine, California, USA

    Kang Chen, Mariam Eghbal-Ahmadi & Tallie Z. Baram

Authors
  1. Kang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ildiko Aradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Niklas Thon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariam Eghbal-Ahmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tallie Z. Baram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ivan Soltesz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ivan Soltesz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, K., Aradi, I., Thon, N. et al. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med 7, 331–337 (2001). https://doi.org/10.1038/85480

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/85480

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