Modelling Epileptic Activity in Hippocampal CA3

  • Sanjay M. 
  • Srinivasa B. KrothapalliEmail author
Part of the Springer Series in Computational Neuroscience book series (NEUROSCI)


This chapter is about developing a computational model of the mechanism of epileptic activity generation in the hippocampal CA3 subfield, a very well-known area that initiates it presumably due to high recurrent connectivity between its constituent neurons, specifically, epileptic activity due to degeneration of OLM interneurons. The model consists of 800 pyramidal neurons, 200 basket and 200 OLM interneurons. The degeneration of OLM interneurons primarily leads to reduced dendritic inhibition on pyramidal neurons. What this leads to is a cascade of network changes including chemical changes as validated by published literature. The biophysical features of the model are explained, and how these changes lead to epileptic activity is described and modelled. Such a proposed model would help to investigate if the progression to epileptic activity generation can be contained at some stage. This could imply a therapeutic strategy for validation using further experimental studies, hence the relevance of the model.


Temporal lobe epilepsy Hippocampus Oscillations Depolarization block Basket cells Computer model 


  1. Amaral DG (1993) Emerging principles of intrinsic hippocampal organization. Curr Opin Neurobiol 3:225–229CrossRefGoogle Scholar
  2. Barbarosie M, Avoli M (1997) CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J Neurosci 17(23):9308–9314CrossRefGoogle Scholar
  3. Bikson M, Hahn PJ, Fox JE, Jefferys JGR (2003) Depolarization block of neurons during maintenance of electrographic seizures. J Neurophysiol 90:2402–2408CrossRefGoogle Scholar
  4. Borhegyi Z, Varga V, Szilágyi N, Fabo D, Freund TF (2004) Phase segregation of medial septal GABAergic neurons during hippocampal theta activity. J Neurosci 24(39):8470–8479CrossRefGoogle Scholar
  5. Carnevale NT, Hines ML (2006) The NEURON book. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  6. Cobb SR, Halasy K, Vida KI, Nyiri G, Tamas G, Buhl EH, Somogyi P (1997) Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus. Neuroscience 79(3):629–648CrossRefGoogle Scholar
  7. Colgin LL, Moser EI (2010) Gamma oscillations in the hippocampus. Physiology 25:319–329CrossRefGoogle Scholar
  8. Cooke SF, Bliss TVP (2006) Plasticity in the human central nervous system. Brain 129:1659–1673CrossRefGoogle Scholar
  9. Cossart R, Dinocourt C, Hirsch JC, Merchan-Perez A, De Felipe J, Ben-Ari Y, Esclapez M, Bernard C (2001) Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy. Nat Neurosci 4(1):52–62CrossRefGoogle Scholar
  10. Curley AA, Lewis DA (2012) Cortical basket cell dysfunction in schizophrenia. J Physiol 590(4):715–724CrossRefGoogle Scholar
  11. Cymerblit-Sabba A, Schiller Y (2012) Development of hypersynchrony in the cortical network during chemoconvulsant-induced epileptic seizures in vivo. J Neurophysiol 107:1718–1730CrossRefGoogle Scholar
  12. Destexhe A, Rudolph M, Paré D (2003) The high-conductance state of neocortical neurons in vivo. Nat Rev Neurosci 4:739–751CrossRefGoogle Scholar
  13. Dinocourt C, Petanjek Z, Freund TF, Ben-Ari Y, Esclapez M (2003) Loss of interneurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine-induced seizures. J Comp Neurol 459:407–425CrossRefGoogle Scholar
  14. Dragoi G, Carpi D, Recce M, Csicsvari J, Buzsáki G (1999) Interactions between hippocampus and medial septum during sharp waves and theta oscillation in the behaving rat. J Neurosci 19(14):6190–6199CrossRefGoogle Scholar
  15. Dudek EF, Staley KJ (2007) How does the balance of excitation and inhibition shift during epileptogenesis? Epilepsy Curr 7(3):86–88CrossRefGoogle Scholar
  16. Dzhala VI, Staley KJ (2003) Transition from interictal to ictal activity in limbic networks in vitro. J Neurosci 23(21):7873–7880CrossRefGoogle Scholar
  17. El-Hassar L, Milh M, Wendling F, Ferrand N, Esclapez M, Bernard C (2007) Cell domain-dependent changes in the glutamatergic and GABAergic drives during epileptogenesis in the Rat CA1 region. J Physiol 578(Pt 1):193–211CrossRefGoogle Scholar
  18. Furman M (2013) Seizure initiation and propagation in the pilocarpine rat model of temporal lobe epilepsy. J Neurosci 33(42):16409–16411CrossRefGoogle Scholar
  19. Gloveli T, Dugladze T, Rotstein HG, Traub RD, Monyer H, Heinemann U, Whittington MA, Kopell NJ (2005) Orthogonal arrangement of rhythm-generating microcircuits in the hippocampus. PNAS 102(37):13295–13300CrossRefGoogle Scholar
  20. Hangya B, Borhegyi Z, Szilagyi N, Freund T, Varga V (2009) GABAergic neurons of the medial septum lead the hippocampal network during theta activity. J Neurosci 29:8094–8102CrossRefGoogle Scholar
  21. Hines ML, Davison AP, Muller E (2009) NEURON and Python. Front Neuroinform 3:2009CrossRefGoogle Scholar
  22. Id Bihi R, Jefferys JGR, Vreugdenhil M (2005) The role of extracellular potassium in the epileptogenic transformation of recurrent GABAergic inhibition. Epilepsia 46(Suppl. 5):64–71CrossRefGoogle Scholar
  23. Isaev D, Isaeva E, Khazipov R, Holmes GL (2007) Shunting and hyperpolarizing GABAergic inhibition in the high-potassium model of ictogenesis in the developing rat hippocampus. Hippocampus 17(3):210–219CrossRefGoogle Scholar
  24. Karlocai MR, Kohus Z, Kali S, Ulbert I, Szabo G, Mate Z, Freund TF, Gulyas AI (2014) Physiological sharp wave-ripples and interictal events in vitro: what's the difference? Brain 137:463–485CrossRefGoogle Scholar
  25. Leite JP, Neder L, Arisi GA, Carlotti CG Jr, Assirati A, Moreira E (2005) Plasticity, synaptic strength, and epilepsy: what can we learn from ultrastructural data? Epilepsia 46(Suppl. 5):134–141CrossRefGoogle Scholar
  26. Lytton WW (2008) Computer modelling of epilepsy. Nat Rev Neurosci 9:626–637CrossRefGoogle Scholar
  27. Lytton WW, Orman R, Stewart M (2005) Computer simulation of epilepsy: implications for seizure spread and behavioral dysfunction. Epilepsy Behav 7(3):336–344CrossRefGoogle Scholar
  28. Manganotti P, Miniussi C, Santorum E, Tinazzi M, Bonato C, Marzi CA, Fiaschi A, Bernardina DB, Zanette G (1998) Influence of somatosensory input on paroxysmal activity in benign rolandic epilepsy with ‘extreme somatosensory evoked potentials’. Brain 121:647–658CrossRefGoogle Scholar
  29. McAllister KA (2000) Cellular and molecular mechanisms of dendritic growth. Cereb Cortex 10:963–973CrossRefGoogle Scholar
  30. Mora GN, Bramanti P, Osculati F, Chakir A, Nicolato E, Marzola P, Sbarbati A, Fabene PF (2009) Does pilocarpine-induced epilepsy in adult rats require status epilepticus? PLoS One 4(6):e5759CrossRefGoogle Scholar
  31. Neymotin SA, Lazarewicz MT, Sherif M, Contreras D, Finkel LH, Lytton WW (2011) Ketamine disrupts theta modulation of gamma in a computer model of hippocampus. J Neurosci 31(32):11733–11743CrossRefGoogle Scholar
  32. Neymotin SA, Hilscher MM, Moulin TC, Skolnick Y, Lazarewicz MT et al (2013) Ih tunes Theta/gamma oscillations and cross-frequency coupling in an in silico CA3 model. PLoS One 8(10):e76285. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ren, Ye-Jun Shi, Qin-Chi Lu, Pei-Ji Liang, Pu-Ming Zhang (2014) The role of the entorhinal cortex in epileptiform activities of the hippocampus. Theor Biol Med Model 11:14CrossRefGoogle Scholar
  34. Sanjay M, Neymotin SA, Krothapalli SB (2015) Impaired dendritic inhibition leads to epileptic activity in a computer model of CA3. Hippocampus 25:1336–1350CrossRefGoogle Scholar
  35. Seddigh S, Thomke F, Vogt TH (1999) Complex partial seizures provoked by photic stimulation. J Neurol Neurosurg Psychiatry 66:801–802CrossRefGoogle Scholar
  36. Sloviter RS, Zappone CA, Harvey BD, Bumanglag AV, Bender RA, Frotscher M (2003) “Dormant basket cell” hypothesis revisited: relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat. J Comp Neurol 459(1):44–76CrossRefGoogle Scholar
  37. Stacey W, Lazarewicz M, Litt B (2009) Synaptic noise and physiological coupling generate high-frequency oscillations in a hippocampal computational model. J Neurophysiol 102:2342–2357CrossRefGoogle Scholar
  38. Stewart M, Fox SE (1990) Do septal neurons pace the hippocampal theta rhythm? Trends Neurosci 13:163–168CrossRefGoogle Scholar
  39. Stoop R, Pralong E (2000) Functional connections and epileptic spread between hippocampus, entorhinal cortex and amygdala in a modified horizontal slice preparation of the rat brain. Eur J Neurosci 12:3651–3663CrossRefGoogle Scholar
  40. Tort AB, Rotstein HG, Dugladze T, Gloveli T, Kopell NJ (2007) On the formation of gamma-coherent cell assemblies by oriens lacunosum moleculare interneurons in the hippocampus. Proc Natl Acad Sci U S A 104:13490–13495CrossRefGoogle Scholar
  41. White J, Banks MI, Pearce R, Kopell N (2000) Networks of interneurons with fast and slow γ-aminobutyric acid type A (GABAA) kinetics provide substrate for mixed gamma-theta rhythm. Proc Natl Acad Sci 97:8128–8133CrossRefGoogle Scholar
  42. Whittington MA, Traub RD, Jefferys JGR (1995) Erosion of inhibition contributes to the progression of low magnesium bursts in rat hippocampal slices. J Physiol 486(3):723–734CrossRefGoogle Scholar
  43. Witter MP (2007) Intrinsic and extrinsic wiring of CA3: implications for connectional heterogeneity. Learn Mem 14:705–713CrossRefGoogle Scholar
  44. Wittner L, Eross L, Czirják S, Halász P, Freund TF, Maglóczky Z (2005) Surviving CA1 pyramidal cells receive intact perisomatic inhibitory input in the human epileptic hippocampus. Brain 128:138–152CrossRefGoogle Scholar
  45. Zhang W, Buckmaster PS (2009) Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy. J Neurosci 29(24):7846–7856CrossRefGoogle Scholar
  46. Ziburkus J, Cressman JR, Barreto E, Schiff SJ (2006) Interneuron and pyramidal cell interplay during in vitro seizure-like events. J Neurophysiol 95:3948–3954CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Neurophysiology Unit, Department of Neurological SciencesChristian Medical CollegeVelloreIndia
  2. 2.Department of BioengineeringChristian Medical CollegeVelloreIndia
  3. 3.Department of Electrical EngineeringNational Institute of Technology CalicutKattangalIndia
  4. 4.Neurophysiology Unit, Department of Neurological SciencesChristian Medical CollegeVelloreIndia

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