[Frontiers in Bioscience, Elite, 8, 390-411, June 1, 2016]

Immediate epileptogenesis: Impact on brain in C57BL/6J mouse kainate model

Sreekanth Puttachary 1 , Shaunik Sharma 1 , Achala Thippeswamy 1 , Thimmasettappa Thippeswamy 1

1Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames IA 50011-1250, USA


1. Abstract
2. Introduction
3. Materials and methods
    3.1. Animal source and ethics statement
    3.2. Chemicals and reagents
    3.3. Mild and severe SE induction with kainate and the experimental groups
        3.3.1. Cortical EEG acquisition with continuous video EEG monitoring and analysis
    3.4. Morris Water Maze test and quantification
        3.4.1. Fixed platform cue learning in Morris water maze
        3.4.2. Training
        3.4.3. Probe trial
    3.5. MRI and quantification
    3.6. Tissue processing for histology and IHC
        3.6.1. Immunopositive cell quantification
    3.7. Statistics
4. Results
    4.1. The epileptiform spike rate and the frequency of spontaneous CS increase with the severity of SE during the first two weeks after the SE
    4.2. Electrographic features of epileptogenesis: Characteristics of post-diazepam EEG, pre-, post-, and inter-ictal spikes, and NCS clusters during the first two weeks of post-SE
    4.3. Impact of epileptiform spiking and spontaneous CS on brain pathology at 7, 14 and 28 day post-SE
    4.4. Impact of epileptiform spiking, spontaneous CS and electrographic NCS, and brain pathology on hippocampal dependent discriminatory learning and memory
5. Discussion
6. Acknowledgement
7. References


We have recently demonstrated immediate epileptogenesis in the C57BL/6J mouse, the strain that is resistant to kainate-induced neurotoxicity. By using a repeated low dose of kainate, we produced mild and severe status epilepticus (SE) models. In the present study, we demonstrate the impact of mild and severe SE, and spontaneous convulsive/nonconvulsive seizures (CS/NCS) on structure and function of the hippocampus, entorhinal cortex, and amygdala at 7, 14 and 28 day post-SE. Immunohistochemistry (IHC) of brain sections confirmed reactive astrogliosis and microgliosis, neurodegeneration, and increased neurogenesis in both groups. The epileptiform spike rate was higher in the severe group during first 12 days, but they decreased thereafter. Morris water maze test confirmed cognitive deficit in both mild and severe groups at 12d post-SE. However, MRI and IHC at 18 weeks did not reveal any changes in the hippocampus. These findings suggest that in C57BL/6J mice, immediate spontaneous CS could be responsible for early brain pathology or vice versa, however, the persistent spontaneous NCS for a long-term had no impact on the brain structure in both groups.


1. P. E. Schauwecker: The effects of glycemic control on seizures and seizure-induced excitotoxic cell death. BMC Neurosci, 13, 94 (2012)
DOI: 10.1186/1471-2202-13-94

2. P. E. Schauwecker and O. Steward: Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci U S A, 94 (8), 4103-8 (1997)
DOI: 10.1073/pnas.94.8.4103

3. G. M. McKhann, 2nd, H. J. Wenzel, C. A. Robbins, A. A. Sosunov and P. A. Schwartzkroin: Mouse strain differences in kainic acid sensitivity, seizure behavior, mortality, and hippocampal pathology. Neuroscience, 122(2), 551-61 (2003)
DOI: 10.1016/S0306-4522(03)00562-1

4. J. Yang, B. Houk, J. Shah, K. F. Hauser, Y. Luo, G. Smith, E. Schauwecker and G. N. Barnes: Genetic background regulates semaphorin gene expression and epileptogenesis in mouse brain after kainic acid status epilepticus. Neuroscience, 131(4), 853-69 (2005)
DOI: 10.1016/j.neuroscience.2004.09.064

5. P. E. Schauwecker: Genetic basis of kainate-induced excitotoxicity in mice: phenotypic modulation of seizure-induced cell death. Epilepsy Res, 55(3), 201-10 (2003)
DOI: 10.1016/S0920-1211(03)00115-3

6. S. A. Benkovic, J. P. O’Callaghan and D. B. Miller: Regional neuropathology following kainic acid intoxication in adult and aged C57BL/6J mice. Brain Res, 1070(1), 215-31 (2006)
DOI: 10.1016/j.brainres.2005.11.065

7. M. C. McCord, A. Lorenzana, C. S. Bloom, Z. O. Chancer and P. E. Schauwecker: Effect of age on kainate-induced seizure severity and cell death. Neuroscience, 154(3), 1143-53 (2008)
DOI: 10.1016/j.neuroscience.2008.03.082

8. S. Puttachary, S. Sharma, K. Tse, E. Beamer, A. Sexton, J. Crutison and T. Thippeswamy: Immediate Epileptogenesis after Kainate-Induced Status Epilepticus in C57BL/6J Mice: Evidence from Long Term Continuous Video-EEG Telemetry. PLoS One, 10(7), e0131705 (2015)
DOI: 10.1371/journal.pone.0131705

9. K. Tse, S. Puttachary, E. Beamer, G. J. Sills and T. Thippeswamy: Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies. PLoS One, 9(5), e96622 (2014)
DOI: 10.1371/journal.pone.0096622

10. P. S. Buckmaster and A. L. Jongen-Relo: Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats. J Neurosci, 19(21), 9519-29 (1999)

11. M. S. Rao, B. Hattiangady, D. S. Reddy and A. K. Shetty: Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy. J Neurosci Res, 83(6), 1088-105 (2006)
DOI: 10.1002/jnr.20802

12. A. P. Le and W. J. Friedman: Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J Neurosci, 32(2), 703-12 (2012)
DOI: 10.1523/JNEUROSCI.4128-11.2012

13. K. M. Chiu, C. C. Wu, M. J. Wang, M. Y. Lee and S. J. Wang: Protective effects of bupivacaine against kainic acid-induced seizure and neuronal cell death in the rat hippocampus. Biol Pharm Bull, 38(4), 522-30 (2015)
DOI: 10.1248/bpb.b14-00633

14. J. M. Parent and D. H. Lowenstein: Seizure-induced neurogenesis: are more new neurons good for an adult brain? Prog Brain Res, 135, 121-31 (2002)
DOI: 10.1016/S0079-6123(02)35012-X

15. D. K. Binder and C. Steinhauser: Functional changes in astroglial cells in epilepsy. Glia, 54(5), 358-68 (2006)
DOI: 10.1002/glia.20394

16. M. L. Olsen and H. Sontheimer: Functional implications for Kir4.1. channels in glial biology: from K+ buffering to cell differentiation. J Neurochem, 107(3), 589-601 (2008)
DOI: 10.1111/j.1471-4159.2008.05615.x

17. J. Wetherington, G. Serrano and R. Dingledine: Astrocytes in the epileptic brain. Neuron, 58(2), 168-78 (2008)
DOI: 10.1016/j.neuron.2008.04.002

18. W. Zhang, R. Yamawaki, X. Wen, J. Uhl, J. Diaz, D. A. Prince and P. S. Buckmaster: Surviving hilar somatostatin interneurons enlarge, sprout axons, and form new synapses with granule cells in a mouse model of temporal lobe epilepsy. J Neurosci, 29(45), 14247-56 (2009)
DOI: 10.1523/JNEUROSCI.3842-09.2009

19. N. C. de Lanerolle, T. S. Lee and D. D. Spencer: Astrocytes and epilepsy. Neurotherapeutics, 7(4), 424-38 (2010)
DOI: 10.1016/j.nurt.2010.08.002

20. G. Seifert, G. Carmignoto and C. Steinhauser: Astrocyte dysfunction in epilepsy. Brain Res Rev, 63(1-2), 212-21 (2009)
DOI: 10.1016/j.brainresrev.2009.10.004

21. J. Kessler and H. J. Markowitsch: Different neuropathological effects of intrahippocampal injections of kainic acid and tetanus toxin. Experientia, 39(8), 922-4 (1983)
DOI: 10.1007/BF01990440

22. W. A. Turski, E. A. Cavalheiro, Z. A. Bortolotto, L. M. Mello, M. Schwarz and L. Turski: Seizures produced by pilocarpine in mice: a behavioral, electroencephalographic and morphological analysis. Brain Res, 321(2), 237-53 (1984)
DOI: 10.1016/0006-8993(84)90177-X

23. Y. Ben-Ari and R. Cossart: Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci, 23(11), 580-7 (2000)
DOI: 10.1016/S0166-2236(00)01659-3

24. I. Knuesel, V. Riban, R. A. Zuellig, M. C. Schaub, R. M. Grady, J. R. Sanes and J. M. Fritschy: Increased vulnerability to kainate-induced seizures in utrophin-knockout mice. Eur J Neurosci, 15(9), 1474-84 (2002)
DOI: 10.1046/j.1460-9568.2002.01980.x

25. C. Huneau, P. Benquet, G. Dieuset, A. Biraben, B. Martin and F. Wendling: Shape features of epileptic spikes are a marker of epileptogenesis in mice. Epilepsia, 54(12), 2219-27 (2013)
DOI: 10.1111/epi.12406

26. R. J. Racine: Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 32(3), 281-94 (1972)
DOI: 10.1016/0013-4694(72)90177-0

27. R. Morris: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods, 11(1), 47-60 (1984)
DOI: 10.1016/0165-0270(84)90007-4

28. C. V. Vorhees and M. T. Williams: Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc, 1(2), 848-58 (2006)
DOI: 10.1038/nprot.2006.116

29. C. A. Schneider, W. S. Rasband and K. W. Eliceiri: NIH Image to Image J: 25 years of image analysis. Nat Methods, 9(7), 671-5 (2012)
DOI: 10.1038/nmeth.2089

30. A. S. Cosgrave, J. S. McKay, V. Bubb, R. Morris, J. P. Quinn and T. Thippeswamy: Regulation of activity-dependent neuroprotective protein (ADNP) by the NO-cGMP pathway in the hippocampus during kainic acid-induced seizure. Neurobiol Dis, 30(3), 281-92 (2008)
DOI: 10.1016/j.nbd.2008.02.005

31. E. Beamer, J. Otahal, G. J. Sills and T. Thippeswamy: N (w) -propyl-L-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses. Eur J Neurosci, 36(9), 3194-203 (2012)
DOI: 10.1111/j.1460-9568.2012.08234.x

32. A. S. Cosgrave, J. S. McKay, R. Morris, J. P. Quinn and T. Thippeswamy: The effects of nitric oxide inhibition prior to kainic acid treatment on neuro-and gliogenesis in the rat dentate gyrus in vivo and in vitro. Histol Histopathol, 25(7), 841-56 (2010)

33. L. C. Schmued and J. F. Bowyer: Methamphetamine exposure can produce neuronal degeneration in mouse hippocampal remnants. Brain Res, 759(1), 135-40 (1997)
DOI: 10.1016/S0006-8993(97)00173-X

34. L. C. Schmued and K. J. Hopkins: Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res, 874(2), 123-30 (2000)
DOI: 10.1016/S0006-8993(00)02513-0

35. M. S. Todorovic, M. L. Cowan, C. A. Balint, C. Sun and J. Kapur: Characterization of status epilepticus induced by two organophosphates in rats. Epilepsy Res, 101(3), 268-76 (2012)
DOI: 10.1016/j.eplepsyres.2012.04.014

36. A. S. Cosgrave, J. S. McKay and T. Thippeswamy: Differential regulation of vasoactive intestinal peptide (VIP) in the dentate gyrus and hippocampus via the NO-cGMP pathway following kainic acid-induced seizure in the rat. J Mol Neurosci, 42(3), 359-69 (2010)
DOI: 10.1007/s12031-010-9353-x

37. M. J. Carson, J. Crane and A. X. Xie: Modeling CNS microglia: the quest to identify predictive models. Drug Discov Today Dis Models, 5(1), 19-25 (2008)
DOI: 10.1016/j.ddmod.2008.07.006

38. D. S. Davis and M. J. Carson: An introduction to CNS-Resident Microglia: Definitions, Assays and Functional Roles in Health and Disease. Springer Press, (2013)

39. V. C. Kurschner, R. L. Petruzzi, G. T. Golden, W. H. Berrettini and T. N. Ferraro: Kainate and AMPA receptor binding in seizure-prone and seizure-resistant inbred mouse strains. Brain Res, 780(1), 1-8 (1998)
DOI: 10.1016/S0006-8993(97)01081-0

40. J. P. McLin, L. M. Thompson and O. Steward: Differential susceptibility to striatal neurodegeneration induced by quinolinic acid and kainate in inbred, outbred and hybrid mouse strains. Eur J Neurosci, 24 (11), 3134-40 (2006)
DOI: 10.1111/j.1460-9568.2006.05198.x

41. P. E. Schauwecker: The relevance of individual genetic background and its role in animal models of epilepsy. Epilepsy Res, 97(1-2), 1-11 (2011)
DOI: 10.1016/j.eplepsyres.2011.09.005

42. P. A. Williams, A. M. White, S. Clark, D. J. Ferraro, W. Swiercz, K. J. Staley and F. E. Dudek: Development of spontaneous recurrent seizures after kainate-induced status epilepticus. J Neurosci, 29(7), 2103-12 (2009)
DOI: 10.1523/JNEUROSCI.0980-08.2009

43. K. J. Staley, A. White and F. E. Dudek: Interictal spikes: harbingers or causes of epilepsy? Neurosci Lett, 497(3), 247-50 (2011)
DOI: 10.1016/j.neulet.2011.03.070

44. D. M. de Groot, E. P. Bierman, P. L. Bruijnzeel, P. Carpentier, B. M. Kulig, G. Lallement, B. P. Melchers, I. H. Philippens and A. H. van Huygevoort: Beneficial effects of TCP on soman intoxication in guinea pigs: seizures, brain damage and learning behaviour. J Appl Toxicol, 21 Suppl 1, S57-65 (2001)
DOI: 10.1002/jat.812

45. T. Ravizza, M. Rizzi, C. Perego, C. Richichi, J. Veliskova, S. L. Moshe, M. G. De Simoni and A. Vezzani: Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia, 46 Suppl 5, 113-7 (2005)
DOI: 10.1111/j.1528-1167.2005.01006.x

46. A. Vezzani, T. Ravizza, S. Balosso and E. Aronica: Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia, 49 Suppl 2, 24-32 (2008)
DOI: 10.1111/j.1528-1167.2008.01490.x

47. M. de Araujo Furtado, F. Rossetti, S. Chanda and D. Yourick: Exposure to nerve agents: from status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy. Neurotoxicology, 33(6), 1476-90 (2012)
DOI: 10.1016/j.neuro.2012.09.001

48. J. Jiang, M. S. Yang, Y. Quan, P. Gueorguieva, T. Ganesh and R. Dingledine: Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol Dis, 76, 126-36 (2015)
DOI: 10.1016/j.nbd.2014.12.032

49. G. M. Arisi, M. L. Foresti, K. Katki and L. A. Shapiro: Increased CCL2, CCL3, CCL5, and IL-1beta cytokine concentration in piriform cortex, hippocampus, and neocortex after pilocarpine-induced seizures. J Neuroinflammation, 12(1), 129 (2015)
DOI: 10.1186/s12974-015-0347-z

50. P. Carpentier, I. S. Delamanche, M. Le Bert, G. Blanchet and C. Bouchaud: Seizure-related opening of the blood-brain barrier induced by soman: possible correlation with the acute neuropathology observed in poisoned rats. Neurotoxicology, 11(3), 493-508 (1990)

51. R. Kovacs, U. Heinemann and C. Steinhauser: Mechanisms underlying blood-brain barrier dysfunction in brain pathology and epileptogenesis: role of astroglia. Epilepsia, 53 Suppl 6, 53-9 (2012)
DOI: 10.1111/j.1528-1167.2012.03703.x

52. U. Heinemann, D. Kaufer and A. Friedman: Blood-brain barrier dysfunction, TGFbeta signaling, and astrocyte dysfunction in epilepsy. Glia, 60(8), 1251-7 (2012)
DOI: 10.1002/glia.22311

53. H. J. Shin, H. Kim, R. W. Heo, H. J. Kim, W. S. Choi, H. M. Kwon and G. S. Roh: Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-kappaB-mediated neuroinflammation in kainic acid-induced seizures. Cell Death Differ, 21(7), 1095-106 (2014)
DOI: 10.1038/cdd.2014.29

54. F. Frigerio, A. Frasca, I. Weissberg, S. Parrella, A. Friedman, A. Vezzani and F. M. Noe: Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology. Epilepsia, 53(11), 1887-97 (2012)
DOI: 10.1111/j.1528-1167.2012.03666.x

55. L. A. Shapiro, M. J. Korn, Z. Shan and C. E. Ribak: GFAP-expressing radial glia-like cell bodies are involved in a one-to-one relationship with doublecortin-immunolabeled newborn neurons in the adult dentate gyrus. Brain Res, 1040(1-2), 81-91 (2005)
DOI: 10.1016/j.brainres.2005.01.098

56. M. B. Gibbons, R. M. Smeal, D. K. Takahashi, J. R. Vargas and K. S. Wilcox: Contributions of astrocytes to epileptogenesis following status epilepticus: opportunities for preventive therapy? Neurochem Int, 63(7), 660-9 (2012)
DOI: 10.1016/j.neuint.2012.12.008

57. S. Robel, S. C. Buckingham, J. L. Boni, S. L. Campbell, N. C. Danbolt, T. Riedemann, B. Sutor and H. Sontheimer: Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci, 35(8), 3330-45 (2015)
DOI: 10.1523/JNEUROSCI.1574-14.2015

58. A. Bordey and H. Sontheimer: Passive glial cells, fact or artifact? J Membr Biol, 166(3), 213-22 (1998)
DOI: 10.1007/s002329900463

59. A. Bordey, S. A. Lyons, J. J. Hablitz and H. Sontheimer: Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia. J Neurophysiol, 85(4), 1719-31 (2001)

60. A. Volterra and J. Meldolesi: Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci, 6(8), 626-40 (2005)
DOI: 10.1038/nrn1722

61. C. Steinhauser and G. Seifert: Astrocyte dysfunction in epilepsy. Brain Res Rev, 63(1-2), 212-21 (2010)
DOI: 10.1016/j.brainresrev.2009.10.004

62. T. Eid, N. Tu, T. S. Lee and J. C. Lai: Regulation of astrocyte glutamine synthetase in epilepsy. Neurochem Int, 63(7), 670-81 (2013)
DOI: 10.1016/j.neuint.2013.06.008

63. F. J. Perez-Asensio, O. Hurtado, M. C. Burguete, M. A. Moro, J. B. Salom, I. Lizasoain, G. Torregrosa, J. C. Leza, E. Alborch, J. Castillo, R. G. Knowles and P. Lorenzo: Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia. Neurobiol Dis, 18(2), 375-84 (2005)
DOI: 10.1016/j.nbd.2004.10.018

64. M. Jafarian-Tehrani, G. Louin, N. C. Royo, V. C. Besson, G. A. Bohme, M. Plotkine and C. Marchand-Verrecchia: 1400W, a potent selective inducible NOS inhibitor, improves histopathological outcome following traumatic brain injury in rats. Nitric Oxide, 12(2), 61-9 (2005)
DOI: 10.1016/j.niox.2004.12.001

65. E. Aronica, U. S. Sandau, A. Iyer and D. Boison: Glial adenosine kinase--a neuropathological marker of the epileptic brain. Neurochem Int, 63(7), 688-95 (2013)
DOI: 10.1016/j.neuint.2013.01.028

66. R. C. Gupta, D. Milatovic and W. D. Dettbarn: Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: protection by antioxidants. Neurotoxicology, 22(2), 271-82 (2001)
DOI: 10.1016/S0161-813X(01)00013-4

67. R. C. Gupta, D. Milatovic and W. D. Dettbarn: Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E. Arch Toxicol, 75(6), 346-56 (2001)
DOI: 10.1007/s002040100249

68. H. Ischiropoulos: Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys, 356(1), 1-11 (1998)
DOI: 10.1006/abbi.1998.0755

69. M. J. Bianchetta, T. T. Lam, S. N. Jones and M. A. Morabito: Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. J Neurosci, 31(33), 12029-35 (2011)
DOI: 10.1523/JNEUROSCI.2388-11.2011

70. C. Liu, Y. Li, P. J. Lein and B. D. Ford: Spatiotemporal patterns of GFAP upregulation in rat brain following acute intoxication with diisopropylfluorophosphate (DFP). Curr Neurobiol, 3(2), 90-97 (2012)

71. J. M. Parent, R. C. Elliott, S. J. Pleasure, N. M. Barbaro and D. H. Lowenstein: Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol, 59(1), 81-91 (2006)
DOI: 10.1002/ana.20699

72. J. M. Parent, T. W. Yu, R. T. Leibowitz, D. H. Geschwind, R. S. Sloviter and D. H. Lowenstein: Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci, 17(10), 3727-38 (1997)

73. P. Mohapel, C. T. Ekdahl and O. Lindvall: Status epilepticus severity influences the long-term outcome of neurogenesis in the adult dentate gyrus. Neurobiol Dis, 15(2), 196-205 (2004)
DOI: 10.1016/j.nbd.2003.11.010

74. F. Yang, J. C. Wang, J. L. Han, G. Zhao and W. Jiang: Different effects of mild and severe seizures on hippocampal neurogenesis in adult rats. Hippocampus, 18(5), 460-8 (2008)
DOI: 10.1002/hipo.20409

75. V. Bouilleret, V. Ridoux, A. Depaulis, C. Marescaux, A. Nehlig and G. Le Gal La Salle: Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience, 89(3), 717-29 (1999)
DOI: 10.1016/S0306-4522(98)00401-1

76. Y. W. Hung, D. I. Yang, P. Y. Huang, T. S. Lee, T. B. Kuo, C. H. Yiu, Y. H. Shih and Y. Y. Lin: The duration of sustained convulsive seizures determines the pattern of hippocampal neurogenesis and the development of spontaneous epilepsy in rats. Epilepsy Res, 98(2-3), 206-15 (2012)
DOI: 10.1016/j.eplepsyres.2011.09.015

77. P. Jiruska, A. B. Shtaya, D. M. Bodansky, W. C. Chang, W. P. Gray and J. G. Jefferys: Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy. Neurobiol Dis, 54, 492-8 (2013)
DOI: 10.1016/j.nbd.2013.02.001

78. K. O. Cho, Z. R. Lybrand, N. Ito, R. Brulet, F. Tafacory, L. Zhang, L. Good, K. Ure, S. G. Kernie, S. G. Birnbaum, H. E. Scharfman, A. J. Eisch and J. Hsieh: Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun, 6, 6606 (2015)
DOI: 10.1038/ncomms7606

79. H. E. Scharfman, J. H. Goodman and A. L. Sollas: Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci, 20(16), 6144-58 (2000)

80. B. L. Murphy, R. Y. Pun, H. Yin, C. R. Faulkner, A. W. Loepke and S. C. Danzer: Heterogeneous integration of adult-generated granule cells into the epileptic brain. J Neurosci, 31(1), 105-17 (2011)
DOI: 10.1523/JNEUROSCI.2728-10.2011

81. H. E. Scharfman, A. E. Sollas, R. E. Berger, J. H. Goodman and J. P. Pierce: Perforant path activation of ectopic granule cells that are born after pilocarpine-induced seizures. Neuroscience, 121(4), 1017-29 (2003)
DOI: 10.1016/S0306-4522(03)00481-0

82. S. C. Danzer, X. He, A. W. Loepke and J. O. McNamara: Structural plasticity of dentate granule cell mossy fibers during the development of limbic epilepsy. Hippocampus, 20(1), 113-24 (2009)
DOI: 10.1002/hipo.20589

83. L. Danglot, A. Triller and S. Marty: The development of hippocampal interneurons in rodents. Hippocampus, 16(12), 1032-60 (2006)
DOI: 10.1002/hipo.20225

84. K. W. Henderson, J. Gupta, S. Tagliatela, E. Litvina, X. Zheng, M. A. Van Zandt, N. Woods, E. Grund, D. Lin, S. Royston, Y. Yanagawa, G. B. Aaron and J. R. Naegele: Long-term seizure suppression and optogenetic analyses of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J Neurosci, 34(40), 13492-504 (2014)
DOI: 0.1523/JNEUROSCI.0005-14.2014

85. J. N. Lugo, J. W. Swann and A. E. Anderson: Early-life seizures result in deficits in social behavior and learning. Exp Neurol, 256, 74-80 (2014)
DOI: 10.1016/j.expneurol.2014.03.014

86. J. A. Witt and C. Helmstaedter: Cognition in the early stages of adult epilepsy. Seizure, 26, 65-8 (2015)
DOI: 10.1016/j.seizure.2015.01.018

87. A. P. Jellett, K. Jenks, M. Lucas and R. C. Scott: Standard dose valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy. Epilepsy Res, 110, 88-94 (2015)
DOI: 10.1016/j.eplepsyres.2014.11.005

88. A. R. Brooks-Kayal, K. G. Bath, A. T. Berg, A. S. Galanopoulou, G. L. Holmes, F. E. Jensen, A. M. Kanner, T. J. O’Brien, V. H. Whittemore, M. R. Winawer, M. Patel and H. E. Scharfman: Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia, 54 Suppl 4, 44-60 (2013)
DOI: 10.1111/epi.12298

89. J. K. Kleen, R. C. Scott, G. L. Holmes, D. W. Roberts, M. M. Rundle, M. Testorf, P. P. Lenck-Santini and B. C. Jobst: Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology, 81(1), 18-24 (2013)
DOI: 10.1212/WNL.0b013e318297ee50

90. G. L. Holmes: EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy. Epilepsia, 54 Suppl 2, 60-2 (2013)
DOI: 10.1111/epi.12186

91. G. L. Holmes: Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord, 17(2), 101-16 (2015)

Key Words: Epileptogenesis, Gliosis, Neurodegeneration, Neurogenesis, Cognitive Deficits

Send correspondence to: Thimmasettappa Thippeswamy, Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames IA 50011-1250, USA, Tel: 515-294-2571, Fax: 515-294-2315 E-mail: tswamy@iastate.edu