Seizures occur more frequently early in life. Some of these early seizures may eventually become epilepsy. Others are reactive seizures due to excessive environmental stimuli that, in any other age group, might not have elicited a similar response. To understand the developmental aspects of seizures and epilepsy in humans, it is important to study these processes in animals of equivalent ages. In this paper, we describe several animal models of developmental seizures, including their electroclinical manifestations and their validity in respect to human epileptic syndromes. There are several factors that may account for the increased seizure susceptibility of the immature brain, including the delayed development of effective systems or synaptic networks that are involved in the suppression of seizures. A better insight of the basic pathophysiology of seizures as a function of age in animal models will lead to the development of new therapeutic approaches for the treatment of age-specific epileptic disorders in humans. (J Child Neurol 1994;9(Suppl):S3-S11).
Get full access to this article
View all access options for this article.
References
1.
Annegers JF: The epidemiology of epilepsy, in Wyllie E (ed): The Treatment of Epilepsy: Principles and Practices . Philadelphia, Lea & Febiger , 1993, pp 157-170.
2.
Hauser WA, Kurland LT:The epidemiology of epilepsy in Rochester, Minnesota, 1935-1967. Epilepsia1975;16:1-66.
3.
Ferngren H., Paalzow L.: High-frequency electroshock seizures and their antagonisms during postnatal development in the mouse. I. Parameters for electroshock and effect of diphenylhydantoin . Acta Pharmacol Toxicol1969;27:237-248.
4.
Millichap JG , Balter M., Hernandez P.: Development of susceptibility to seizures in young animals: III. Brain water, electrolyte and acid-base metabolism. Proc Soc Exp Biol Med1959;99:6-11.
5.
Mareš P., Trojan S.: Ontogenetic development of isonicotinehydrazide-induced seizures in rats. Brain Dev1991;13:121-125.
6.
Mareš P., Kubová H., Czuczwar SJ: Aminophylline exhibits convulsant action in rats during ontogenesis. Brain Dev (In press).
7.
Velišek L., Kubová H., Pohl M., et al: Pentylenetetrazol-induced seizures in rats: An ontogenetic study. Naunyn Schmiedebergs Arch Pharmacol1992;346:588-591.
8.
de Casrilevitz M., Engelhardt E., Esberard CA:Maturation of convulsogenic activity induced by leptazol in the albino rat. Br J PharmacoL1971;42:31-42.
9.
de Feo M., Mecarelli O., Ricci G.:Bicuculline- and allyglycineinduced epilepsy in developing rats. Exp Neurol1985;90:411-421.
10.
Zouhar A., Mareš P., Lisková-Bernásková K., et al: Motor and electrocorticographic epileptic activity induced by bicuculline in developing rats. Epilepsia1989;30:501-510.
11.
Mareš P., Kubová H., Zouhar A., et al.: Motor and electrocorticographic epileptic activity induced by 3-mercaptopropionic acid in immature rats. Epilepsy Res1993;16:11-18.
12.
Kubová H., Mareš P.: Different postnatal development of convulsions and lethality induced by strychnine in rats. Pharmacol Toxicol (In press).
13.
Sperber EF, Moshé SL: Age-related differences in seizure susceptibility to flurothyl. DevelopBrain Res1988;39:295-297.
14.
Mareš P., Lisková-Bernásková K., Mudrochová M.: Ontogenetic development of convulsant action of Ro 5-3663 in the rat. Life Sci1987;40:1161-1170.
15.
Schickerová R., Mareš P., Trojan S.: Correlation between electrocorticographic and motor phenomena induced by Metrazol during ontogenesis in rats. Exp Neurol1984;84:153-164.
16.
Löscher W., Schmidt D.: Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res1988;2: 145-181.
17.
Swinyard EA: Assay of antiepileptic drug activity in experimental animals, in Mercier J (ed): International Encyklopedia of Pharmacology and Therapeutics. Oxford, Pergamon Press, 1973, pp 47-65.
18.
Kubová H., Mareš P.: Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats. Epilepsy Res1991; 10:148-155.
19.
Stankova L. , Mareš P., Zouhar A., et al: Ontogenic development of convulsant action of picrotoxin in the rat. Physiol Bohemoslov1988;37:571.
20.
Gloor P., Testa G., Guberman A.: Brainstem and cortical mechanisms in an animal model of generalized corticoreticular epilepsy. Trans Am Neurol Assoc1973;98:203-205.
21.
Prince D., Farrell D.: "Centrencephalic" spike-wave discharges following parenteral penicillin injection in the cat. Neurology1969;19:309-310.
22.
Schickerová R., Mareš P., Trojan S.: Rhythmic metrazol activity in rats as a model of human absences. Act Nerv Super (Praha ) 1989;31:16-20.
23.
Zouhar A., Mareš P., Brozek G.: Electrocorticographic activity elicited by Metrazol during ontogenesis in rats. Arch Int Pharmacodyn Ther1980;248:280-288.
24.
Kubová H., Mareš P.: Convulsant action of a benzodiazepine receptor agonist/inverse agonist Ro 19-4603 in developing rats. Naunyn Schmiedebergs Arch Pharmacol (In press).
25.
Snead OCIII: Ontogeny of gamma-hydroxybutyric acid. II. Electroencephalographic effects . Brain Res1984;317:89-96.
26.
Vergnes M., Marescaux C., Depaulis A., et al: Ontogeny of spontaneous petit mal-like seizures in Wistar rats. DevelopBrain Res1986;30:85-87.
27.
Serikawa T. , Yamada J., Ujihara H., et al: Ontogeny of absence-like and tonic seizures in the spontaneously epileptic rat. Lab Anim1991;25:216-221.
28.
Woodbury DM: Convulsants. Convulsant drugs: Mechanisms of action, in Glaser GH, Penry JK, Woodbury DM (eds): Antiepileptic Drugs: Mechanisms of Action. New York, Raven Press, 1980, pp 249-304.
29.
Pohl M., Mareš P.: Flunarizine influences Metrazol-induced seizures in developing rats . Epilepsy Res1987;1:302-305.
30.
Reed MD, Besunder JB: Developmental pharmacology: ontogenic basis of drug disposition. Pediatr Clin North Am1989;36: 1053-1074.
31.
Joo F.: Current aspects of the development of the blood-brain barrier. Int J Dev Neurosci1987;5:369-372.
32.
Saunders NR, Mollgard K.: Development of the blood-brain barrier. J Dev Physiol1984;6:45-57.
33.
Mareš P., Chino M., Kubová H., et al: Glutamate and bicuculline methiodide enter the brain of immature rats. Physiol Res1992;41:9.
34.
Moshé SL: Seizure in the developing brain. Neurology1993;43 (Suppl 5):S3-S7.
35.
Bishop EJ: The strychnine spike as a physiological indicator of cortical maturity in the postnatal rabbit. Electroenceph Clin Neurophysiol1950;2:309-315.
36.
Mareš P.: Symmetrical epileptogenic foci in cerebral cortex of immature rat. Epilepsia1973;14:427-435.
37.
Mareš P.: Ontogenetic development of bioelectrical activity of the epileptogenic focus in rat neocortex. Neuropaediatrie1973; 4:434-445.
38.
Velišková J., Velišek L., Mareš P.: Epileptic phenomena produced by kainic acid in laboratory rats during ontogenesis. Physiol Bohemoslov1988;37:395-405.
39.
Soukupova S. , Mikolasova R., Kubová H., et al: New model of cortical epileptic foci in freely moving developing rats. Epilepsy Res1993;15:27-33.
40.
Ward AA: Topical convulsant metals, in Purpura DP, Penry KJ, Tower DB , et al (eds): Experimental Models of Epilepsy. New York, Raven Press , 1972, pp 13-36.
41.
Lewin E.: The production of epileptogenic cortical foci in experimental animals by freezing , in Purpura DP, Penry KJ, Tower DB , et al (eds): Experimental Models of Epilepsy. New York, Raven Press, 1972, pp 38-50.
Schoepp DD, Gamble AY, Salhof CR, et al: Excitatory amino acid-induced convulsions in neonatal rats mediated by distinct receptor subtypes. Eur J Pharmacol1990;182:421-427.
44.
Cavalheiro EA, Silva DF, Turski WA, et al: The susceptibility of rats to pilocarpine-induced seizures is age dependent. DevelopBrain Res1987;37:43-58.
45.
Ben-Ari Y., Tremblay E., Riche D., et al: Electrographic, clinical, and pathological alterations following systemic administration of kainic acid, bicuculline, or pentetrazole: Metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience1981;6:1361-1391.
46.
Ben-Ari Y.:Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience1985;14:375-403.
Nadler JV: Kainic acid as a tool for the study of tempolar lobe epilepsy. Life Sci1981;29:2031-2042.
49.
Albala BJ, Moshé SL, Okada R.: Kainic-acid-induced seizures: A developmental study. DevelopBrain Res1984;13:139-148.
50.
Okada R., Moshé SL, Albala BJ: Infantile status epilepticus and future seizure susceptibility in the rat. DevelopBrain Res1984;15: 177-183.
51.
Cavalheiro LA, Riche DA,Le Gal La Salle G.:Long-term effects of intrahippocampal kainic acid injection in rats: A method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol1982;53:581-589.
52.
Thompson JL , Stafstrom CE, Chronopoulos A., et al: Effect of age on seizure susceptibility following kainic acid-induced status epilepticus . Epilepsia1990;31:634.
53.
Marešová D., Mareš P.: Ontogenetic development of wet dog shakes accompanying hippocampal epileptic after-discharges in rats. Act Nerv Super (Praha) 1988 ;30:254.
54.
Overmann SR , Zimmer L., Woolley DE: Electroconvulsive shock elicits wet-dog shakes and face washing in preweaning rats. Physiol Behav1982;29:1025-1037.
Goddard GV, McIntyre DC, Leech CK: A permanent change in brain function resulting from daily electrical stimulation . Exp Neurol1969;25:295-330.
57.
Moshé SL, Ludvig N.: Kindling, in Pedley TA, Meldrum BS (eds): Recent Advances in Epilepsy . Edinburgh, Churchhill Livingstone , 1988, pp 21-44.
58.
Engel JJ, Ackermann RF, Caldecott-Hazard S., et al: Epileptic activation of antagonistic systems may explain paradoxical features of experimental and human epilepsy: A review and hypothesis, in Wada JA (ed): Kindling 2. New York, Raven Press, 1981, pp 193-217.
59.
Racine RJ: Modification of seizure activity by electrical stimulation: I. After discharge threshold. Electroencephalogr Clin Neurophysiol1972;32:269-279.
60.
Cain DP, Corcoran ME: Kindling with low frequency stimulation: Generality, transfer, and recruiting effects. Exp Neurol1981;73:219-232.
61.
Lothman EW, Hatlelid JM, Zorumski CF, et al: Kindling with rapidly recurring hippocampal seizures. Brain Res1985;360: 83-91.
62.
Racine R.: Kindling: The first decade. Neurosurgery1978 ;3: 234-252.
63.
Moshé SL, Albala BJ: Maturational changes in postictal refractoriness and seizure susceptibility in developing rats. Ann Neurol1983;13:552-557.
64.
Burchfiel JL , Applegate CD: Stepwise progression of kindling: Perspectives from the kindling antagonism model, in Cain DP, Teskey D (eds): Neuroscience and Biobehavioral Reviews. New York, Pergamon, 1989, pp 289-308.
65.
Burchfiel JL , Applegate CD, Konkol RJ: Kindling antagonism: A role for norepinephrine in seizure suppression, in Wada JA (ed): Kindling 3 . New York, Raven Press, 1986, pp 213-229.
66.
Applegate CD , Konkol RJ, Burchfiel JL: Kindling antagonism: A role for hindbrain norepinephrine in the development of site suppression following concurrent, alternate stimulation. Brain Res1987;407:212-222.
Wada JA, Sato M., Corcoran ME: Persistent seizure susceptibility and recurrent spontaneous seizures in kindled cats. Epilepsia1974;15:465-478.
69.
Burnham WM: Cortical and limbic kindling: Similarities and differences, in Livingston KE, Hornykiewicz O (eds): Limbic Mechanisms. The Continuing Evolution of the Limbic System Concept. New York, Plenum Press, 1978, pp 507-519.
70.
Moshé SL, Cornblath M.: Developmental aspects of epileptogenesis, in Wyllie E (ed): The Treatment of Epilepsy: Principles and Practice. Philadelphia, Lea & Febiger, 1993, pp 99-110.
71.
Mareš P., Kubová H., Haugvicova R.: Transition between two types of epileptic seizures in developing rats as a sign of progressive epileptogenesis. Epilepsy Res (In press).
72.
Moshé SL, Albala BJ, Ackermann RF, et al: Increased seizure susceptibility of the immature brain. DevelopBrain Res1983;7: 81-85.
73.
Lee S., Murata R., Matsuura S.: The developmental study of hippocampal kindling. Epilepsia1989;30:266-270.
74.
Haas K., Sperber EF, Moshé SL: Kindling in developing animals: Expression of severe seizures and enhanced development of bilateral foci. DevelopBrain Res1990;56:275-280.
75.
Sperber EF, Haas K., Moshé SL: Mechanisms of kindling in developing animals, in Wada JA (ed): Kindling 4. New York, Plenum Press, 1990, pp 157-168.
76.
Haas K., Sperber EF, Moshé SL: Kindling in developing animals: Interactions between ipsilateral foci. DevelopBrain Res1992; 68:140-143.
Coyle JT, Enna SJ: Neurochemical aspects of the ontogenesis of gabanergic neurons in the rat brain. Brain Res1976;111: 119-133.
79.
Swann JW, Brady RJ, Smith KL, et al: Synaptic mechanisms of focal epileptogenesis in the immature nervous system, in Swann JW, Messer A (eds): Disorders of the Developing Nervous System: Changing View on Their Origins, Diagnoses, and Treatment. New York, Alan R. Liss, 1988, pp 19-49.
80.
Roberts E., Kuriyama K.: Biochemical-physiological correlations in studies of the gamma-aminobutyric acid system. Brain Res1968;8:1-35.
81.
Roberts E.: Gamma-aminobutyric acid and nervous function: A perspective. Biochem Pharmacol1974;23:2637-2649.
82.
Tobin AJ: Molecular biological approaches to the synthesis and action of GABA . Semin Neurosci1991;3:183-190.
83.
Erlander MG , Tobin AJ: The structural and functional heterogenity of glutamic acid decarboxylase. Neurochem Res1991;16:215-226.
84.
Seress L., Ribak CE: The development of GABAergic neurons in the rat hippocampal formation. An immunocytochemical study. DevelopBrain Res1988;44:197-210.
85.
Kunkel DD, Hendrickson AE, Wu JY, et al: Glutamic acid decarboxylase (GAD) immunocytochemistry of developing rabbit hippocampus. J Neurosci1986;6:541-552.
86.
Seress L., Frotscher M., Ribak CE: Local circuit neurons in both the dentate gyrus and Ammon's horn establish synaptic connections with principal neurons in five day old rats: A morphological basis for inhibition in early development. Exp Brain Res1989; 78:1-9.
87.
Madtes PJ: Ontogeny of the GABA receptor complex, in Reburn DA, Schousboe AAR (eds): Neurotrophic Activity of GABA During Development. New York , Alan R. Liss, 1987, pp 161-187.
88.
Möhler H., Malherbe P., Draguhn A., et al: GABAA-receptors: Structural requirements and sites of gene expression in mammalian brain. Neurochem Res1990;15:199-207.
89.
Levitan ES, Schofield PR, Burt DR, et al: Structural and functional basis for GABAA receptor heterogenity . Nature1988;335:76-79.
90.
MacLennan AJ , Brecha N., Khrestchatisky M., et al: Independent cellular and ontogenetic expression of mRNAs encoding three a polypeptides of the rat GABAA receptor. Neuroscience1991 ; 43:369-380.
91.
Laurie DJ, Wisden W., Seeburg PH: The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci1992; 12:4151-4172.
92.
Gambarana C. , Beattie CE, Rodriguez ZR, et al: Region-specific expression of messenger RNAs encoding GABAA receptor subunits in the developing rat brain. Neuroscience1991;45:423-432.
93.
Wu W., Ziskind-Conheim L., Sweet MA: Early development of glycine- and GABA-mediated synapses in rat spinal cord . J Neurosci1992;12:3935-3945.
94.
Becker C-M. , Hoch W., Betz H.: Glycine receptor heterogenity in rat spinal cord during postnatal development. EMBO J1988;7: 3717-3726.
95.
Young AB, Fagg GF: Excitatory amino acid receptors in the brain: Membrane binding and receptor autoradiographic approaches. Trends Pharmacol Sci1990;11:126-133.
96.
Insel TR, Miller RP, Gelhard RE:The ontogeny of excitatory amino acid receptors in rat forebrain, I. N-methyl-D-aspartate receptors and quisqualate receptors. Neuroscience1990;35:31-43.
97.
Tremblay E. , Roisin MP, Represa A., et al: Transient increased density of NMDA binding sites in the developing rat hippocampus. Brain Res1988;461:393-396.
98.
Miles R., Wong RKS: Inhibitory control of local excitatory circuits in the guinea pig hippocampus . J Physiol (London) 1987;388: 611-629.
99.
Brady RJ, Smith KL, Swann JW: Calcium modulation of the N-methyl-D-aspartate (NMDA) response and electrographic seizures in immature hippocampus. Neurosci Lett1991;124: 92-96.
100.
Corcoran ME, Weiss GK: Noradrenaline and kindling revisited, in Wada JA (ed): Kindling 4. New York, Plenum Press, 1990, pp 141-153.
101.
McIntyre DC: Catecholamine involvement in amygdala kindling of the rat, in Wada JA (ed): Kindling 2 . New York, Raven Press, 1981, pp 67-79.
102.
Applegate CD, Burchfiel JL: Evidence for a norepinephrine-dependent brain-stem substrate in the development of kindling antagonism. Epilepsy Res1990;6:23-32.
103.
Davison AN: The biochemistry of the myelin sheath, in Davison AN, Peters A (eds): Myelination. Springfield, IL, Thomas , 1970, pp 80-161.
104.
Agrawal HC, Davison AN: Myelination and aminoacid imbalance in the developing brain, in Himwich W (ed): Biochemistry of the Developing Brain. New York, Dekker, 1973, pp 143-168.
105.
Eayrs JT, Goodhead B.: Postnatal development of the cerebral cortex in the rat. J Anat1959;93:385-402.
106.
Connors BE , Ransom BR, Kunis DM, et al: Activity-dependent K+ accumulation in the developing rat optic nerve. Science1982;216:1341-1343.
107.
Hablitz JJ , Heinemann U.: Extracellular K+ and Ca2+ changes during epileptiform discharges in the immature rat neocortex. Brain Res1987;433:299-303.
108.
Mutani R., Futamachi KJ, Prince DA: Potassium activity in immature cortex. Brain Res1984; 75:27-39.
109.
Traynelis SF, Dingledine R.: Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol1988;59:259-276.
110.
Hablitz JJ , Heinemann U.: Alterations in the microenvironment during spreading depression associated with epileptiform activity in the immature neocortex. DevelopBrain Res1989;46:243-252.
111.
Moshé SL, Sperber EF: Substantia nigra-mediated control of generalized seizures, in Gloor G, Kostopoulos R, Naquet M, Avoli P (eds): Generalized Epilepsy: Cellular, Molecular, and Pharmacological Approaches. Boston, Birkhauser, 1990, pp 355-367.
112.
Engel JJ, Brown LL, Wolfson L.: Anatomical correlates of electrical and behavioral events related to amygdaloid kindling. Ann Neurol1978;3:538-544.
113.
Ackermann RF, Moshé SL, Albala BJ: Restriction of enhanced 14C-2-deoxyglucose utilization to rhinencephalic structures in immature amygdala-kindled rats . Exp Neurol1989;104:73-81.
114.
Ackermann RF, Sperber EF, Haas K., et al: Anatomical substrates of severe kindled limbic seizures in immature rats. A radiolabeled deoxyglucose and glucose study. Epilepsia1990; 31:676-000.
115.
Moshé SL, Albala BJ: Nigral muscimol infusions facilitate the development of seizures in immature rats. DevelopBrain Res1984;13:305-308.
116.
Sperber EF , Wong BY, Wurpel JND, et al: Nigral infusions of muscimol or bicuculline facilitate seizures in developing rats. DevelopBrain Res1987;37:243-250.
117.
Sperber EF , Wurpel JND, Moshé SL: Evidence for the involvement of nigral GABAB receptors in seizures in rat pups. DevelopBrain Res1989;47:143-146.
118.
Velišková J., Velišek L., Ptachewich Y., et al: Baclofen is anticonvulsant in 15-day-old and older rats but proconvulsant in 9-day-old rat pups. Electroencephalogr Clin Neurophysiol1993;87:45.
