Modeling Early-Onset Postischemic Seizures in Adult and Aging Mice

  • Liang ZhangEmail author
  • Chiping Wu
  • Justin Wang
Part of the Neuromethods book series (NM, volume 152)


Stroke is the most common cause of seizures in the adult and elderly population. The development of seizures after stroke is known to be associated with poorer prognoses including higher rates of disability and mortality. Currently, the pathophysiology of how these post-stroke seizures develop and why they occur in certain patients but not in others is not well understood. The use of prophylactic antiepileptics/anticonvulsants after stroke and its unproven role in preventing late-onset poststroke seizures remains a contentious issue. Our recent experiments have focused on examining early-onset postischemic seizures in adult and aging mice using a middle cerebral artery occlusion model and a hypoxia–ischemia model. We focused on electroencephalographic recordings, characterization and detection of convulsive and nonconvulsive seizures, assessment of histological brain injury, and the role of anticonvulsant treatment. Here we discuss these experiments in the hopes that our experience may further future investigations in mouse models of postischemic seizures and other neurological diseases.

Key words

Aging Anticonvulsant Convulsion EEG Epilepsy Ischemia Mouse model Seizure Stroke 



This research was supported by the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Epilepsy Research Program of the Ontario Brain Institute. The authors thank Ms. Nila Sivanenthiran for editing the manuscript.


  1. 1.
    Bladin CF, Bornstein N (2009) Post-stroke seizures. In: Fisher M (ed) Stroke Part II: Clinical manifestations and pathogenesis. Handbook of clinical neurology, vol 93. Elsevier B.V., pp 613–621Google Scholar
  2. 2.
    Brodie MJ, Elder AT, Kwan P (2009) Epilepsy in later life. Lancet Neurol 8:1019–1030PubMedCrossRefGoogle Scholar
  3. 3.
    Menon B, Shorvon SD (2009) Ischaemic stroke in adults and epilepsy. Epilepsy Res 87:1–11PubMedCrossRefGoogle Scholar
  4. 4.
    Chen RL, Balami JS, Esiri MM et al (2010) Ischemic stroke in the elderly: an overview of evidence. Nat Rev Neurol 6:256–265PubMedCrossRefGoogle Scholar
  5. 5.
    Balami JS, Chen RL, Grunwald IQ et al (2011) Neurological complications of acute ischaemic stroke. Lancet Neurol 10:357–371PubMedCrossRefGoogle Scholar
  6. 6.
    Gilad R (2012) Management of seizures following a stroke. What are the options? Drugs Aging 29:533–538PubMedCrossRefGoogle Scholar
  7. 7.
    Guekht A, Bornstein NM (2012) Seizures after stroke. In: Stefan H, Theodore WH (eds) Epilepsy. Handbook of clinical neurology, vol 108. Elsevier (3rd series), pp 570–583Google Scholar
  8. 8.
    Procaccianti G, Zaniboni A, Rondelli F et al (2012) Seizures in acute stroke: incidence, risk factors and prognosis. Neuroepidemiology 39:45–50PubMedCrossRefGoogle Scholar
  9. 9.
    Guth JC, Gerard EE, Nemeth AJ (2014) Subarachnoid extension of hemorrhage is associated with early seizures in primary intracerebral hemorrhage. J Stroke Cerebrovasc Dis 23:2809–2813PubMedCrossRefGoogle Scholar
  10. 10.
    Mani R, Schmitt SE, Mazer M et al (2012) The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia. Resuscitation 83:840–847PubMedCrossRefGoogle Scholar
  11. 11.
    Rittenberger JC, Popescu A, Brenner RP et al (2012) Frequency and timing of nonconvulsive status epilepticus in comatose post-cardiac arrest subjects treated with hypothermia. Neurocrit Care 16:114–122PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Knight WA, Hart KW, Adeoye OM et al (2013) The incidence of seizures in patients undergoing therapeutic hypothermia after resuscitation from cardiac arrest. Epilepsy Res 106:396–402PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Hofmeijer J, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A et al (2014) Unstandardized treatment of electroencephalographic status epilepticus does not improve outcome of comatose patients after cardiac arrest. Front Neurol 5:39PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Waterhouse EJ, Vaughan JK, Barnes TY et al (1998) Synergistic effect of status epilepticus and ischemic brain injury on mortality. Epilepsy Res 29:175–183PubMedCrossRefGoogle Scholar
  15. 15.
    Vespa PM, O'Phelan K, Shah M et al (2003) Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome. Neurology 60:1441–1446PubMedCrossRefGoogle Scholar
  16. 16.
    Szaflarski JP, Rackley AY, Kleindorfer DO et al (2008) Incidence of seizures in the acute phase of stroke: a population-based study. Epilepsia 49:974–981PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Burneo JG, Fang J, Saposnik G et al (2010) Impact of seizures on morbidity and mortality after stroke: a Canadian multi-centre cohort study. Eur J Neurol 17:52–58PubMedCrossRefGoogle Scholar
  18. 18.
    Huang CW, Saposnik G, Fang J et al (2014) Influence of seizures on stroke outcomes: a large multicenter study. Neurology 82:768–776PubMedCrossRefGoogle Scholar
  19. 19.
    Kulhari A, Strbian D, Sundararajan S (2014) Early onset seizures in stroke. Stroke 45:e249–e251PubMedCrossRefGoogle Scholar
  20. 20.
    Sykes L, Wood E, Kwan J (2014) Antiepileptic drugs for the primary and secondary prevention of seizures after stroke. Cochrane Database Syst Rev (1):CD005398Google Scholar
  21. 21.
    Mecarelli O, Pro S, Randi F et al (2011) EEG patterns and epileptic seizures in acute phase stroke. Cerebrovasc Dis 31:191–198PubMedCrossRefGoogle Scholar
  22. 22.
    Jordan KG (2004) Emergency EEG and continuous EEG monitoring in acute ischemic stroke. J Clin Neurophysiol 21:341–352PubMedGoogle Scholar
  23. 23.
    Claassen J, Jetté N, Chum F et al (2007) Electrographic seizures and periodic discharges after intracerebral hemorrhage. Neurology 69:1356–1365PubMedCrossRefGoogle Scholar
  24. 24.
    Silverman IE, Restrepo L, Mathews GC (2014) Post stroke seizures. Arch Neurol 59:195–201CrossRefGoogle Scholar
  25. 25.
    Chung JM (2014) Seizures in the acute stroke setting. Neurol Res 36:403–406PubMedCrossRefGoogle Scholar
  26. 26.
    Hartings JA, Williams AJ, Tortella FC (2003) Occurrence of nonconvulsive seizures, periodic epileptiform discharges, and intermittent rhythmic delta activity in rat focal ischemia. Exp Neurol 179:139–149PubMedCrossRefGoogle Scholar
  27. 27.
    Williams AJ, Tortella FC, Lu XM et al (2014) Antiepileptic drug treatment of nonconvulsive seizures induced by experimental focal brain ischemia. J Pharmacol Exp Ther 311:220–227CrossRefGoogle Scholar
  28. 28.
    Williams AJ, Bautista CC, Chen RW et al (2006) Evaluation of gabapentin and ethosuximide for treatment of acute nonconvulsive seizures following ischemic brain injury in rats. J Pharmacol Exp Ther 318:947–955PubMedCrossRefGoogle Scholar
  29. 29.
    Karhunen H, Nissinen J, Sivenius J et al (2006) A long-term video-EEG and behavioral follow-up after endothelin-1 induced middle cerebral artery occlusion in rats. Epilepsy Res 72:25–38PubMedCrossRefGoogle Scholar
  30. 30.
    Lu XC, Si Y, Williams AJ et al (2009) NNZ-2566, a glypromate analog, attenuates brain ischemia-induced non-convulsive seizures in rats. J Cereb Blood Flow Metab 29:1924–1932PubMedCrossRefGoogle Scholar
  31. 31.
    Cuomo O, Rispoli V, Leo A et al (2013) The antiepileptic drug levetiracetam suppresses non-convulsive seizure activity and reduces ischemic brain damage in rats subjected to permanent middle cerebral artery occlusion. PLoS One 8:e80852PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Karhunen H, Bezvenyuk Z, Nissinen J et al (2007) Epileptogenesis after cortical photothrombotic brain lesion in rats. Neuroscience 148:314–324PubMedCrossRefGoogle Scholar
  33. 33.
    Paz JT, Davidson TJ, Frechette ES et al (2013) Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat Neurosci 16:64–70PubMedCrossRefGoogle Scholar
  34. 34.
    Han F, Boller M, Guo W et al (2010) A rodent model of emergency cardiopulmonary bypass resuscitation with different temperatures after asphyxial cardiac arrest. Resuscitation 81:93–99PubMedCrossRefGoogle Scholar
  35. 35.
    Boller M, Jung SK, Odegaard S et al (2011) A combination of metabolic strategies plus cardiopulmonary bypass improves short-term resuscitation from prolonged lethal cardiac arrest. Resuscitation 82(Suppl 2):S27–S34PubMedCrossRefGoogle Scholar
  36. 36.
    Kelly KM, Kharlamov A, Hentosz TM et al (2001) Photothrombotic brain infarction results in seizure activity in aging Fischer 344 and Sprague Dawley rats. Epilepsy Res 47:189–203PubMedCrossRefGoogle Scholar
  37. 37.
    Kelly KM, Shiau DS, Jukkola PI et al (2011) Effects of age and cortical infarction on EEG dynamic changes associated with spike wave discharges in F344 rats. Exp Neurol 232:15–21PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Fluri F, Schuhmann MK, Kleinschnitz C (2015) Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther 9:3445–3454PubMedPubMedCentralGoogle Scholar
  39. 39.
    El-Hayek YH, Wu CP, Chen R et al (2011) Acute post-ischemic seizures are associated with increased mortality and brain damage in adult Mice. Cereb Cortex 21:2863–2875PubMedCrossRefGoogle Scholar
  40. 40.
    Wu CP, Wang J, Peng J et al (2015) Modeling early-onset post-ischemic seizures in aging mice. Exp Neurol 271:1–12PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Wang J, Wu CP, Peng J et al (2015) Early-onset convulsive seizures induced by brain hypoxia-ischemia in aging mice: effects of anticonvulsive treatments. PLoS One 10(12):e0144113PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Flurkey K, Currer JM, Harrison DE (2007) Mouse models in aging research. In: Fox JG, Davisson MT, Quimby FW et al (eds) The mouse in biomedical research. Academic Press, New York, pp 637–672CrossRefGoogle Scholar
  43. 43.
    Wu CP, Wais M, Sheppy E et al (2008) A glue-based, screw-free method for implantation of intra-cranial electrodes in young mice. J Neurosci Meth 171:126–131CrossRefGoogle Scholar
  44. 44.
    Wu CP, Wais M, Zahid T et al (2009) A reliable method for intracranial electrode implantation and chronic electrical stimulation in the mouse brain. Behav Res Meth 41:736–741CrossRefGoogle Scholar
  45. 45.
    Jeffrey M, Lang M, Gane J et al (2013) An improved screw-free method for electrode implantation and intracranial electroencephalographic recordings in mice. BMC Neurosci 14:82PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego, CAGoogle Scholar
  47. 47.
    Wais M, Wu CP, Zahid T et al (2009) Repeated hypoxic episodes induce seizures and alter hippocampal network activities in mice. Neuroscience 161:599–613PubMedCrossRefGoogle Scholar
  48. 48.
    D'Cruz JA, Wu CP, Zahid T et al (2010) Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice. Neurobiol Dis 38:8–16PubMedCrossRefGoogle Scholar
  49. 49.
    Wither RG, Colic S, Wu CP et al (2012) Daily rhythmic behavior and thermoregulatory patterns are disrupted in female MeCP2-deficient mice. PLoS One 7:e35396PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    El-Hayek YH, Wu CP, Zhang L (2011) Early suppression of intracranial EEG signals predicts ischemic outcome in adult mice following hypoxia-ischemia. Exp Neurol 231:295–303PubMedCrossRefGoogle Scholar
  51. 51.
    El-Hayek YH, Wu CP, Ye H et al (2013) Hippocampal excitability is increased in aged mice. Exp Neurol 247:710–719PubMedCrossRefGoogle Scholar
  52. 52.
    Jeffrey M, Lang M, Gane J et al (2014) Novel anticonvulsive effects of progesterone in a mouse model of hippocampal electrical kindling. Neuroscience 257:65–75PubMedCrossRefGoogle Scholar
  53. 53.
    Lang M, Wither RG, Colic S et al (2014) Rescue of behavioral and EEG deficits in male and female Mecp2-deficient mice by delayed Mecp2 gene reactivation. Hum Mol Genet 23:303–318PubMedCrossRefGoogle Scholar
  54. 54.
    Peng J, Li R, Arora N et al (2015) Effects of neonatal hypoxic-ischemic episodes on late seizure outcomes in C57 black mice. Epilepsy Res 111:142–149PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang L, Wither RG, Lang M et al (2016) A role for diminished GABA transporter activity in the cortical discharge phenotype of MeCP2-deficient mice. Neuropsychopharmacology 41:1467–1476PubMedCrossRefGoogle Scholar
  56. 56.
    Durukan A, Tatlisumak T (2007) Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 87:179–197PubMedCrossRefGoogle Scholar
  57. 57.
    Hossmann KA (2008) Cerebral ischemia: models, methods and outcomes. Neuropharmacology 55:257–270PubMedCrossRefGoogle Scholar
  58. 58.
    Sicard KM, Fisher M (2009) Animal models of focal brain ischemia. Exp Transl Stroke Med 1:7PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Howells DW, Porritt MJ, Rewell SS et al (2010) Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J Cereb Blood Flow Metab 30:1412–1431PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Liu FD, McCullough LD (2011) Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J Biomed Biotechnol. Scholar
  61. 61.
    Schmid-Elsaesser R, Zausinger S, Hungerhuber E et al (1998) A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry. Stroke 29:2162–2170PubMedCrossRefGoogle Scholar
  62. 62.
    Vannucci SJ, Willing LB, Goto S et al (2001) Experimental stroke in the female diabetic, db/db, mouse. J Cereb Blood Flow Metab 21:52–60PubMedCrossRefGoogle Scholar
  63. 63.
    Popa-Wagner A, Buga AM, Kokaia Z (2011) Perturbed cellular response to brain injury during aging. Ageing Res Rev 10:71–79PubMedCrossRefGoogle Scholar
  64. 64.
    Zille M, Farr TD, Przesdzing I et al (2011) Visualizing cell death in experimental focal cerebral ischemia: promises, problems, and perspectives. J Cereb Blood Flow Metab 32:213–231PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Schmued LC, Stowers CC, Scallet AC et al (2005) Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res 1035:24–31PubMedCrossRefGoogle Scholar
  66. 66.
    El-Amki M, Clavier T, Perzo N et al (2015) Hypothalamic, thalamic and hippocampal lesions in the mouse MCAO model: potential involvement of deep cerebral arteries? J Neurosci Meth 254:80–85CrossRefGoogle Scholar
  67. 67.
    Meierkord H, Boon P, Engelsen B et al (2010) EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 17:348–355PubMedCrossRefGoogle Scholar
  68. 68.
    Shorvon S (2011) The treatment of status epilepticus. Curr Opin Neurol 24:165–170PubMedCrossRefGoogle Scholar
  69. 69.
    Fujii M, Hara H, Meng W et al (1997) Strain-related differences in susceptibility to transient forebrain ischemia in SV-129 and C57black/6 mice. Stroke 28:1805–1811PubMedCrossRefGoogle Scholar
  70. 70.
    Kitagawa K, Matsumoto M, Yang G et al (1998) Cerebral ischemia after bilateral carotid artery occlusion and intraluminal suture occlusion in mice: evaluation of the patency of the posterior communicating artery. J Cereb Blood Flow Metab 18:570–579PubMedCrossRefGoogle Scholar
  71. 71.
    Ozdemir YG, Bolay H, Erdem E et al (1999) Occlusion of the MCA by an intraluminal filament may cause disturbances in the hippocampal blood flow due to anomalies of circle of Willis and filament thickness. Brain Res 822:260–264PubMedCrossRefGoogle Scholar
  72. 72.
    Majid A, He YY, Gidday JM et al (2003) Differences in vulnerability to permanent focal cerebral ischemia among 3 common mouse strains. Stroke 31:2707–2714CrossRefGoogle Scholar
  73. 73.
    McColl BW, Carswell HV, McCulloch J et al (2004) Extension of cerebral hypoperfusion and ischaemic pathology beyond MCA territory after intraluminal filament occlusion in C57Bl/6J mice. Brain Res 997:15–23PubMedCrossRefGoogle Scholar
  74. 74.
    Adhami F, Liao GH, Morozov YM et al (2006) Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol 169:566–583PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Schauwecker PE, Steward O (1997) Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci U S A 94:4103–4108PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    McKhann GM, Wenzel HJ, Robbins CA et al (2003) Mouse strain differences in kainic acid sensitivity, seizure behavior, mortality, and hippocampal pathology. Neuroscience 122:551–561PubMedCrossRefGoogle Scholar
  77. 77.
    McLin JP, Steward O (2006) Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains. Eur J Neurosci 24:2191–2202PubMedCrossRefGoogle Scholar
  78. 78.
    Kadam SD, White AM, Staley KJ et al (2010) Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy. J Neurosci 30:404–415PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Rakhade SN, Klein PM, Huynh T et al (2011) Development of later life spontaneous seizures in a rodent model of hypoxia-induced neonatal seizures. Epilepsia 52:753–765PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Brandt C, Ebert U, Löscher W (2004) Epilepsy induced by extended amygdala-kindling in rats: lack of clear association between development of spontaneous seizures and neuronal damage. Epilepsy Res 62(2–3):135–156PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Krembil Research Institute, University Health Network, Toronto Western HospitalTorontoCanada
  2. 2.Division of Neurology, Department of MedicineUniversity of TorontoTorontoCanada

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