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Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

Abstract

The mechanisms involved in the transition to an epileptic seizure remain unclear. To examine them, we used tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability along with alkalinization or low Mg2+. During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of subjects with epilepsy revealed that similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster and had larger amplitudes than interictal discharges and had a distinct initiation site. These events depended on glutamatergic mechanisms and were preceded by pyramidal cell firing, whereas interneuron firing preceded interictal events that depended on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggered seizures. Thus, the subiculum supports seizure generation, and the transition to seizure involves an emergent glutamatergic population activity.

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Figure 1: Ictal discharges generated in the human subiculum.
Figure 2: IIDs, PIDs and ictal discharges in intracranial recordings.
Figure 3: PIDs emerge during the transition to ictal-like activity in vitro.
Figure 4: PIDs depend on glutamatergic signaling.
Figure 5: NMDA receptor signaling is involved in seizure generation and in the emergence of PIDs, but not their maintenance.
Figure 6: IIDs and PIDs are generated by distinct networks.
Figure 7: Dynamics of population activity during the transition to ictal events.
Figure 8: Repeated PIDs trigger seizure-like events.

References

  1. Cohen, I., Navarro, V., Clemenceau, S., Baulac, M. & Miles, R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science 298, 1418–1421 (2002).

    Article  CAS  Google Scholar 

  2. Huberfeld, G. et al. Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. J. Neurosci. 27, 9866–9873 (2007).

    Article  CAS  Google Scholar 

  3. de Curtis, M. & Avanzini, G. Interictal spikes in focal epileptogenesis. Prog. Neurobiol. 63, 541–567 (2001).

    Article  CAS  Google Scholar 

  4. Lehnertz, K., Le Van Quyen, M. & Litt, B. Seizure prediction. in Epilepsy: a Comprehensive Textbook (ed. Engel, J. Jr.) (Lippincott Williams & Wilkins, 2007).

  5. Avoli, M. et al. Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro. J. Neurosci. 16, 3912–3924 (1996).

    Article  CAS  Google Scholar 

  6. Gnatkovsky, V., Librizzi, L., Trombin, F. & de Curtis, M. Fast activity at seizure onset is mediated by inhibitory circuits in the entorhinal cortex in vitro. Ann. Neurol. 64, 674–686 (2008).

    Article  Google Scholar 

  7. Miles, R. & Wong, R.K. Single neurones can initiate synchronized population discharge in the hippocampus. Nature 306, 371–373 (1983).

    Article  CAS  Google Scholar 

  8. Ziburkus, J., Cressman, J.R., Barreto, E. & Schiff, S.J. Interneuron and pyramidal cell interplay during in vitro seizure-like events. J. Neurophysiol. 95, 3948–3954 (2006).

    Article  Google Scholar 

  9. Alger, B.E. & Nicoll, R.A. Pharmacological evidence for two kinds of GABA receptor on rat hippocampal pyramidal cells studied in vitro. J. Physiol. (Lond.) 328, 125–141 (1982).

    Article  CAS  Google Scholar 

  10. Kaila, K., Lamsa, K., Smirnov, S., Taira, T. & Voipio, J. Long-lasting GABA-mediated depolarization evoked by high-frequency stimulation in pyramidal neurons of rat hippocampal slice is attributable to a network-driven, bicarbonate-dependent K+ transient. J. Neurosci. 17, 7662–7672 (1997).

    Article  CAS  Google Scholar 

  11. 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 

  12. Derchansky, M. et al. Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation. J. Physiol. (Lond.) 586, 477–494 (2008).

    Article  CAS  Google Scholar 

  13. Trevelyan, A.J., Sussillo, D., Watson, B.O. & Yuste, R. Modular propagation of epileptiform activity: evidence for an inhibitory veto in neocortex. J. Neurosci. 26, 12447–12455 (2006).

    Article  CAS  Google Scholar 

  14. Dzhala, V.I. & Staley, K.J. Transition from interictal to ictal activity in limbic networks in vitro. J. Neurosci. 23, 7873–7880 (2003).

    Article  CAS  Google Scholar 

  15. Jensen, M.S. & Yaari, Y. Role of intrinsic burst firing, potassium accumulation and electrical coupling in the elevated potassium model of hippocampal epilepsy. J. Neurophysiol. 77, 1224–1233 (1997).

    Article  CAS  Google Scholar 

  16. Bartolomei, F., Chauvel, P. & Wendling, F. Epileptogenicity of brain structures in human temporal lobe epilepsy: a quantified study from intracerebral EEG. Brain 131, 1818–1830 (2008).

    Article  Google Scholar 

  17. Bartolomei, F. et al. Pre-ictal synchronicity in limbic networks of mesial temporal lobe epilepsy. Epilepsy Res. 61, 89–104 (2004).

    Article  CAS  Google Scholar 

  18. Spencer, S.S., Guimaraes, P., Katz, A., Kim, J. & Spencer, D. Morphological patterns of seizures recorded intracranially. Epilepsia 33, 537–545 (1992).

    Article  CAS  Google Scholar 

  19. Bragin, A., Azizyan, A., Almajano, J., Wilson, C.L. & Engel, J. Jr. Analysis of chronic seizure onsets after intrahippocampal kainic acid injection in freely moving rats. Epilepsia 46, 1592–1598 (2005).

    Article  Google Scholar 

  20. Gavaret, M., Badier, J.M., Marquis, P., Bartolomei, F. & Chauvel, P. Electric source imaging in temporal lobe epilepsy. J. Clin. Neurophysiol. 21, 267–282 (2004).

    Article  Google Scholar 

  21. Lachaux, J.P., Rudrauf, D. & Kahane, P. Intracranial EEG and human brain mapping. J. Physiol. (Paris) 97, 613–628 (2003).

    Article  Google Scholar 

  22. Clark, K.A. & Collingridge, G.L. Synaptic potentiation of dual-component excitatory postsynaptic currents in the rat hippocampus. J. Physiol. (Lond.) 482, 39–52 (1995).

    Article  CAS  Google Scholar 

  23. Barthó, P. et al. Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J. Neurophysiol. 92, 600–608 (2004).

    Article  Google Scholar 

  24. Pinault, D. A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or Neurobiotin. J. Neurosci. Methods 65, 113–136 (1996).

    Article  CAS  Google Scholar 

  25. Wennberg, R., Arruda, F., Quesney, L.F. & Olivier, A. Preeminence of extrahippocampal structures in the generation of mesial temporal seizures: evidence from human depth electrode recordings. Epilepsia 43, 716–726 (2002).

    Article  Google Scholar 

  26. Fabó, D. et al. Properties of in vivo interictal spike generation in the human subiculum. Brain 131, 485–499 (2008).

    Article  Google Scholar 

  27. Staba, R.J. et al. High-frequency oscillations recorded in human medial temporal lobe during sleep. Ann. Neurol. 56, 108–115 (2004).

    Article  Google Scholar 

  28. Gabriel, S. et al. Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis. J. Neurosci. 24, 10416–10430 (2004).

    Article  CAS  Google Scholar 

  29. Jandová, K. et al. Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices. Brain 129, 3290–3306 (2006).

    Article  Google Scholar 

  30. D'Antuono, M. et al. GABAA receptor–dependent synchronization leads to ictogenesis in the human dysplastic cortex. Brain 127, 1626–1640 (2004).

    Article  CAS  Google Scholar 

  31. Spencer, S.S., Kim, J., deLanerolle, N. & Spencer, D.D. Differential neuronal and glial relations with parameters of ictal discharge in mesial temporal lobe epilepsy. Epilepsia 40, 708–712 (1999).

    Article  CAS  Google Scholar 

  32. Bartolomei, F. et al. Entorhinal cortex involvement in human mesial temporal lobe epilepsy: an electrophysiologic and volumetric study. Epilepsia 46, 677–687 (2005).

    Article  Google Scholar 

  33. Khalilov, I., Holmes, G.L. & Ben-Ari, Y. In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat. Neurosci. 6, 1079–1085 (2003).

    Article  CAS  Google Scholar 

  34. Derchansky, M. et al. Model of frequent, recurrent, and spontaneous seizures in the intact mouse hippocampus. Hippocampus 14, 935–947 (2004).

    Article  CAS  Google Scholar 

  35. Avoli, M. et al. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog. Neurobiol. 68, 167–207 (2002).

    Article  CAS  Google Scholar 

  36. McGonigal, A. et al. Stereoelectroencephalography in presurgical assessment of MRI-negative epilepsy. Brain 130, 3169–3183 (2007).

    Article  Google Scholar 

  37. Chabardès, S. et al. The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain 128, 1818–1831 (2005).

    Article  Google Scholar 

  38. Ebersole, J.S. & Pacia, S.V. Localization of temporal lobe foci by ictal EEG patterns. Epilepsia 37, 386–399 (1996).

    Article  CAS  Google Scholar 

  39. Chassoux, F. et al. Intralesional recordings and epileptogenic zone in focal polymicrogyria. Epilepsia 49, 51–64 (2008).

    Article  Google Scholar 

  40. Wittner, L. & Miles, R. Factors defining a pacemaker region for synchrony in the hippocampus. J. Physiol. 584, 867–883 (2007).

    Article  CAS  Google Scholar 

  41. Menendez de la Prida, L., Suarez, F. & Pozo, M.A. Electrophysiological and morphological diversity of neurons from the rat subicular complex in vitro. Hippocampus 13, 728–744 (2003).

    Article  CAS  Google Scholar 

  42. Miles, R., Traub, R.D. & Wong, R.K. Spread of synchronous firing in longitudinal slices from the CA3 region of the hippocampus. J. Neurophysiol. 60, 1481–1496 (1988).

    Article  CAS  Google Scholar 

  43. Bragin, A., Azizyan, A., Almajano, J. & Engel, J. Jr. The cause of the imbalance in the neuronal network leading to seizure activity can be predicted by the electrographic pattern of the seizure onset. J. Neurosci. 29, 3660–3671 (2009).

    Article  CAS  Google Scholar 

  44. Traynelis, S.F. & Dingledine, R. Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J. Neurophysiol. 59, 259–276 (1988).

    Article  CAS  Google Scholar 

  45. Trevelyan, A.J., Sussillo, D. & Yuste, R. Feedforward inhibition contributes to the control of epileptiform propagation speed. J. Neurosci. 27, 3383–3387 (2007).

    Article  CAS  Google Scholar 

  46. Cohen, I. & Miles, R. Contributions of intrinsic and synaptic activities to the generation of neuronal discharges in in vitro hippocampus. J. Physiol. (Lond.) 524, 485–502 (2000).

    Article  CAS  Google Scholar 

  47. Henze, D.A. et al. Intracellular features predicted by extracellular recordings in the hippocampus in vivo. J. Neurophysiol. 84, 390–400 (2000).

    Article  CAS  Google Scholar 

  48. Le Van Quyen, M. et al. Cell type-specific firing during ripple oscillations in the hippocampal formation of humans. J. Neurosci. 28, 6104–6110 (2008).

    Article  CAS  Google Scholar 

  49. Menendez de la Prida, L., Benavides-Piccione, R., Sola, R. & Pozo, M.A. Electrophysiological properties of interneurons from intraoperative spiking areas of epileptic human temporal neocortex. Neuroreport 13, 1421–1425 (2002).

    Article  Google Scholar 

  50. Le Van Quyen, M. & Bragin, A. Analysis of dynamic brain oscillations: methodological advances. Trends Neurosci. 30, 365–373 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We wish to thank M. Noulhiane for her help with imaging and statistics, M.-L. Tanguy for help with statistical analysis, E. Eugène for his technical assistance, M. Valderrama for software assistance and L. Wittner for participating in initial recordings. We gratefully acknowledge financial support from INSERM, the CNRS, the AP-HP, the Fédération pour la Recherche Médicale, the Fédération pour la Recherche sur le Cerveau, the Agence Nationale de la Recherche, the European Community (EPICURE, LSH-037315), Spain-France Joint Action (HF2006-0082), the Spanish National Research Council (Consejo Superior de Investigaciones Científicas 200720I023) and the Spanish Ministry of Innovation and Science (BFU2006-10584-BFI and BFU2009-07989).

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G.H., L.M.d.l.P. and R.M. designed the study. G.H., L.M.d.l.P. and R.M. performed the in vitro experiments. G.H., S.C., J.P., C.A. and M.B. performed the in vivo work and analysis. G.H., L.M.d.l.P., J.P., I.C., M.L.V.Q. and R.M. contributed to data analysis. G.H. and R.M. wrote the paper.

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Correspondence to Gilles Huberfeld or Richard Miles.

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Huberfeld, G., Menendez de la Prida, L., Pallud, J. et al. Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy. Nat Neurosci 14, 627–634 (2011). https://doi.org/10.1038/nn.2790

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