Advertisement

Journal of Computational Neuroscience

, Volume 47, Issue 2–3, pp 125–140 | Cite as

Modeling cortical spreading depression induced by the hyperactivity of interneurons

  • Mathieu Desroches
  • Olivier Faugeras
  • Martin KrupaEmail author
  • Massimo Mantegazza
Article
  • 167 Downloads

Abstract

Cortical spreading depression (CSD) is a wave of transient intense neuronal firing leading to a long lasting depolarizing block of neuronal activity. It is a proposed pathological mechanism of migraine with aura. Some forms of migraine are associated with a genetic mutation of the Nav1.1 channel, resulting in its gain of function and implying hyperexcitability of interneurons. This leads to the counterintuitive hypothesis that intense firing of interneurons can cause CSD ignition. To test this hypothesis in silico, we developed a computational model of an E-I pair (a pyramidal cell and an interneuron), in which the coupling between the cells in not just synaptic, but takes into account also the effects of the accumulation of extracellular potassium caused by the activity of the neurons and of the synapses. In the context of this model, we show that the intense firing of the interneuron can lead to CSD. We have investigated the effect of various biophysical parameters on the transition to CSD, including the levels of glutamate or GABA, frequency of the interneuron firing and the efficacy of the KCC2 co-transporter. The key element for CSD ignition in our model was the frequency of interneuron firing and the related accumulation of extracellular potassium, which induced a depolarizing block of the pyramidal cell. This constitutes a new mechanism of CSD ignition.

Keywords

Cortical spreading depression Migraine Extracellular potassium Interneuron hyperexcitability 

Notes

Funding Information

European Union projects DESIRE (grant n. EFP7-602531 to MM) and Investissements d’Avenir-Laboratory of Excellence “Ion Channels Science and Therapeutics” (grant LabEx ICST ANR-11-LABX-0015-01 to MM). ERC Advanced Grant Nervi 227747 (to OF).

Compliance with Ethical Standards

Conflict of interests

The authors declare that they have no conflict of interest.

References

  1. Avoli, M., & de Curtis, M. (2011). GABAErgic synchronization in the limbic system and its role in the generation of epileptiform activity. Progress in Neurobiology, 95, 104–132.PubMedPubMedCentralGoogle Scholar
  2. Börgers, C., Epstein, S., Kopell, N. (2005). Background gamma rhythmicity and attention in cortical local circuits: a computational study. Proceedings of the National Academy of Sciences of the United States of America, 102, 7002–7007.PubMedPubMedCentralGoogle Scholar
  3. Capuani, C., Melone, M., Tottene, A., Bragina, L., Crivellaro, G., Santello, M., Casari, G., Conti, F., Pietrobon, D. (2016). Defective glutamate and k+ clearance by cortical astrocytes in familial hemiplegic migraine type 2. EMBO Mol Med e201505944.Google Scholar
  4. Cestèle, S., Scalmani, P., Rusconi, R., Terragni, B., Franceschetti, S., Mantegazza, M. (2008). Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1. 1 (SCN1a) na+ channel. The Journal of Neuroscience, 28, 7273–7283.PubMedPubMedCentralGoogle Scholar
  5. Cestèle, S., Labate, A., Rusconi, R., Tarantino, P., Mumoli, L., Franceschetti, S., Annesi, G., Mantegazza, M., Gambardella, A. (2013). Divergent effects of the T1174S SCN1a mutation associated with seizures and hemiplegic migraine. Epilepsia, 54, 927–935.PubMedGoogle Scholar
  6. Cestèle, S., Schiavon, E., Rusconi, R., Franceschetti, S., Mantegazza, M. (2013). Nonfunctional Nav1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects. Proceedings of the National Academy of Sciences of the United States of America, 110, 17546–17551.PubMedPubMedCentralGoogle Scholar
  7. Chapuisat, G., Dronne, M.A., Grenier, E., Hommel, M., Gilquing, H., Boissel, J.P. (2008). A global phenomenological model of ischemic stroke with stress on spreading depressions. Progress in Biophysics and Molecular Biology, 97, 4–27.PubMedGoogle Scholar
  8. De Fusco, M., Marconi, R., Silvestri, L., Atorino, L., Rampoldi, L., Morgante, L., Ballabio, A., Aridon, P., Casari, G. (2003). Haploinsufficiency of ATP1a2 encoding the na+/k+ pump 2 subunit associated with familial hemiplegic migraine type 2. Nature Genetics, 33, 192–196.PubMedGoogle Scholar
  9. Dahlem, M.A., Schumacher, J., Hübel, N. (2014). Linking a genetic defect in migraine to spreading depression in a computational model. PeerJ, 2, e379.PubMedPubMedCentralGoogle Scholar
  10. Destexhe, A., Mainen, Z.F., Sejnowski, T.J. (1994). An efficient method for computing synaptic conductances based on a kinetic model of receptor binding. Neural Computation, 6, 14–18.Google Scholar
  11. Dichgans, M., Freilinger, T., Eckstein, G., Babini, E., Lorenz-Depiereux, B., Biskup, S., Ferrari, M.D., Herzog, J., van den Maagdenberg, A.M., Pusch, M., Strom, T.M. (2005). Mutation in the neuronal voltage-gated sodium channel SCN1a in familial hemiplegic migraine. Lancet, 366, 371–377.PubMedGoogle Scholar
  12. Doyon, N., Prescott, S.A., Castonguay, A., Godin, A.G., Kröger, H., De Koninck, Y. (2011). Efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis. PLoS Computational Biology, 7, e1002149.PubMedPubMedCentralGoogle Scholar
  13. Dreier, J.P. (2011). The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nature Medicine, 17, 439–447.PubMedGoogle Scholar
  14. Ermentrout, B. (2002). Simulating, analyzing, and animating dynamical systems: a guide to xppaut for researchers and students. SIAM.Google Scholar
  15. Fan, C., & et al. (2016). Early-onset familial hemiplegic migraine due to a novel SCN1a mutation. Cephalalgia, 36(13), 1238–1247.PubMedPubMedCentralGoogle Scholar
  16. Ferrari, M.D., Klever, R.R., Terwindt, G.M., Ayata, C., van den Maagdenberg, A.M. (2015). Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurology, 14, 65–80.PubMedGoogle Scholar
  17. Freund, T.F., & Katona, I. (2007). Perisomatic inhibition. Neuron, 56, 33–42.PubMedGoogle Scholar
  18. Guerrini, R., Marini, C., Mantegazza, M. (2014). Genetic epilepsy syndromes without structural brain abnormalities: Clinical features and experimental models. Neurotherapeutics, 11, 269–285.PubMedPubMedCentralGoogle Scholar
  19. Han, S., Tai, C., Westenbroek, R.E., Yu, F.H., Cheah, C.S., Potter, G.B., Rubenstein, J.L., Scheuer, T., de la Iglesia, H.O., Catterall, W.A. (2012). Autistic-like behaviour in SCN1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nat, 489, 385–390.Google Scholar
  20. Hedrich, U.B., Liautard, C., Kirschenbaum, D., Pofahl, M., Lavigne, J., Liu, Y., Theiss, S., Slotta, J., Escayg, A., Dihne, M., Beck, H., Mantegazza, M., Lerche, H. (2014). Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation. Journal of Neuroscience, 34, 14874–14889.PubMedGoogle Scholar
  21. Kahlig, K.M., Rhodes, T.M., Pusch, M., Freilinger, T., Pereira-Monteiro, J.M., Ferrari, M.D., van den Maagdenberg, A.M., Dichgans, M., George, A.L. Jr. (2008). Divergent sodium channel defects in familial hemiplegic migraine. Proceedings of the National Academy of Sciences of the United States of America, 105, 9799–9804.PubMedPubMedCentralGoogle Scholar
  22. Kaila, K., Price, T.J., Payne, J.A., Puskarjov, M., Voipio, J. (2014). Cation-chloride cotransporters in neuronal development, plasticity and disease. Nature Reviews Neuroscience, 15, 637–654.PubMedPubMedCentralGoogle Scholar
  23. Krishnan, G.P., & Bazhenov, M. (2011). Ionic dynamics mediate spontaneous termination of seizures and postictal depression state. Journal of Neuroscience, 31(24), 8870–8882.PubMedGoogle Scholar
  24. Lauritzen, M. (1994). Pathophysiology of the migraine aura. The spreading depression theory. Brain: A Journal of Neurology, 117, 199–210.Google Scholar
  25. Leo, L., Gherardini, L., Barone, V., De Fusco, M., Pietrobon, D., Pizzorusso, T., Casari, G. (2011). Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genetics, 7, e1002129.PubMedPubMedCentralGoogle Scholar
  26. Lillis, K.P., Kramer, M.A., Mertz, J., Staley, K.J., White, J.A. (2012). Pyramidal cells accumulate chloride at seizure onset. Neurobiology of Disease, 47, 358–366.PubMedPubMedCentralGoogle Scholar
  27. van den Maagdenberg, A.M., Pietrobon, D., Pizzorusso, T., Kaja, S., Broos, L.A., Cesetti, T., van de Ven, R.C., Tottene, A., van der, K.J., Plomp, J.J., Frants, R.R., Ferrari, M.D. (2004). A CACNA1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron, 41, 701–710.PubMedGoogle Scholar
  28. Martins-Ferreira, H., Nedergaard, M., Nicholson, C. (2000). Perspectives on spreading depression. Brain Research Reviews, 32(1), 215–234.PubMedGoogle Scholar
  29. Mantegazza, M., & Cestele, S. (2017). Pathophysiological mechanisms of migraine and epilepsy: Similarities and differences. Neurosci Lett.  https://doi.org/10.1016/j.neulet.2017.11.025.PubMedGoogle Scholar
  30. Mantegazza, M., Curia, G., Biagini, G., Ragsdale, D.S., Avoli, M. (2010). Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurology, 9, 413–424.PubMedGoogle Scholar
  31. Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanagawa, Y., Obata, K., Furuichi, T., Hensch, T.K., Yamakawa, K. (2007). Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an SCN1a gene mutation. Journal of Neuroscience, 27, 5903–5914.PubMedGoogle Scholar
  32. Ophoff, R.A., Terwindt, G.M., Vergouwe, M.N., van Eijk, R., Oefner, P.J., Hoffman, S.M., Lamerdin, J.E., Mohrenweiser, H.W., Bulman, D.E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.J., Hofker, M.H., Ferrari, M.D., Frants, R.R. (1996). Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1a4. Cell, 87, 543–552.PubMedGoogle Scholar
  33. Pietrobon, D., & Moskowitz, M. (2014). Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nature Reviews Neurology, 15, 379–392.Google Scholar
  34. Stafstrom, C.E. (2007). Persistent sodium current and its role in epilepsy. Epilepsy Curr, 7, 15–22.PubMedPubMedCentralGoogle Scholar
  35. Syková, E., & Nicholson, C. (2008). Diffusion in brain extracellular space. Physiological Reviews, 88, 1277–1340.PubMedPubMedCentralGoogle Scholar
  36. Tottene, A., Conti, R., Fabbro, A., Vecchia, D., Shapovalova, M., Santello, M., van den Maagdenberg, A.M., Ferrari, M.D., Pietrobon, D. (2009). Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. Neuron, 61, 762–773.Google Scholar
  37. Traub, R.D., Wong, R.K., Miles, R., Michelson, H. (1991). A model of a CA3 hippocampal pyramidal neuron incorporating voltage-clamp data on intrinsic conductances. Journal of Neurophysiology, 66, 635–650.PubMedGoogle Scholar
  38. Truccolo, W., Donoghue, J.A., Hochberg, L.R., Eskandar, E.N., Madsen, J.R., Anderson, W.S., Brown, E.N., Halgren, E., Cash, S.S. (2011). Single-neuron dynamics in human focal epilepsy. Nature Neuroscience, 14, 635–641.PubMedPubMedCentralGoogle Scholar
  39. Ullah, G., Wei, Y., Dahlem, M.A., Wechselberger, M., Schiff, S.J. (2015). The role of cell volume in the dynamics of seizure, spreading depression, and anoxic depolarization. PLoS Computational Biology, 11, e1004414.PubMedPubMedCentralGoogle Scholar
  40. Vecchia, D., & Pietrobon, D. (2012). Migraine: a disorder of brain excitatory–inhibitory balance? Trends in Neurosciences, 35, 507–520.PubMedGoogle Scholar
  41. Vecchia, D., Tottene, A., van den Maagdenberg, A.M., Pietrobon, D. (2014). Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in Ca2.1 knockin migraine mice. Neurobiology of Disease, 69, 225–234.PubMedPubMedCentralGoogle Scholar
  42. Viitanen, T., Ruusuvuori, E., Kaila, K., Voipio, J. (2010). The K+-Cl cotransporter KCC2 promotes GABAergic excitation in the mature rat hippocampus. Journal of Physiology, 588, 1527–1540.PubMedGoogle Scholar
  43. Wei, Y., Ullah, G., Schiff, S.J. (2014). Unification of neuronal spikes, seizures, and spreading depression. Journal of Neuroscience, 34, 11733–11743.PubMedGoogle Scholar
  44. Wang, X.J., & Buzsáki, G. (1996). Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. Journal of Neuroscience, 16, 6402–6413.PubMedGoogle Scholar
  45. Yu, F.H., Mantegazza, M., Westenbroek, R.E., Robbins, C.A., Kalume, F., Burton, K.A., Spain, W.J., McKnight, G.S., Scheuer, T., Catterall, W.A. (2006). Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience, 9, 1142–1149.PubMedGoogle Scholar
  46. Zandt, B.J., ten Haken, B., van Putten, M.J., Dahlem, M.A. (2015). How does spreading depression spread? Physiology and modeling. Reviews in the Neurosciences, 26, 183–198.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.MathNeuro TeamInria Sophia Antipolis MéditerranéeSophia Antipolis CedexFrance
  2. 2.Université Côte d’AzurNice Cedex 2France
  3. 3.JAD LaboratoryUniversité de Nice Sophia AntipolisNice Cedex 2France
  4. 4.CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC)LabEx ICSTValbonne-Sophia AntipolisFrance

Personalised recommendations