Abstract
Determining the minimal duration of status epilepticus (SE) that leads to the development of subsequent spontaneous seizures (i.e., epilepsy) is important, because it provides a critical time-window for seizure intervention and epilepsy prevention. In the present study, male ICR (Imprinting Control Region) mice were injected with pilocarpine to induce acute seizures. SE was terminated by diazepam at 10 min, 30 min, 1 h, 2 h and 4 h after seizure onset. Spontaneous seizures occurred in the 1, 2 and 4 h SE groups, and the seizure frequency increased with the prolongation of SE. Similarly, the Morris water maze revealed that the escape latency was significantly increased and the number of target quadrant crossings was markedly decreased in the 1, 2 and 4 h SE groups. Robust mossy fiber sprouting was observed in these groups, but not in the 10 or 30 min group. In contrast, Fluoro-Jade B staining revealed significant cell death only in the 4 h SE group. The incidence and frequency of spontaneous seizures were correlated with Timm score (P = 0.004) and escape latency (P = 0.004). These data suggest that SE longer than one hour results in spontaneous motor seizures and memory deficits, and spontaneous seizures are likely associated with robust mossy fiber sprouting but not neuronal death.
Keywords: epileptogenesis, pilocarpine, Fluoro-Jade B staining, Timm staining, Morris water maze
References
- [1].Shorvon SD. The causes of epilepsy: changing concepts of etiology of epilepsy over the past 150 years. Epilepsia. 2011;52:1033–1044. doi: 10.1111/j.1528-1167.2011.03051.x. [DOI] [PubMed] [Google Scholar]
- [2].Dudek FE, Spitz M. Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis: proposed role of synaptic reorganization. J Clin Neurophysiol. 1997;14:90–101. doi: 10.1097/00004691-199703000-00002. [DOI] [PubMed] [Google Scholar]
- [3].Bernard C, Anderson A, Becker A, Poolos NP, Beck H, Johnston D. Acquired dendritic channelopathy in temporal lobe epilepsy. Science. 2004;305:532–535. doi: 10.1126/science.1097065. [DOI] [PubMed] [Google Scholar]
- [4].Zhang W, Huguenard JR, Buckmaster PS. Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy. J Neurosci. 2012;32:1183–1196. doi: 10.1523/JNEUROSCI.5342-11.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Cavalheiro EA, Santos NF, Priel MR. The pilocarpine model of epilepsy in mice. Epilepsia. 1996;37:1015–1019. doi: 10.1111/j.1528-1157.1996.tb00541.x. [DOI] [PubMed] [Google Scholar]
- [6].Muller CJ, Bankstahl M, Groticke I, Loscher W. Pilocarpine vs. lithium-pilocarpine for induction of status epilepticus in mice: development of spontaneous seizures, behavioral alterations and neuronal damage. Eur J Pharmacol. 2009;619:15–24. doi: 10.1016/j.ejphar.2009.07.020. [DOI] [PubMed] [Google Scholar]
- [7].Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972;32:281–294. doi: 10.1016/0013-4694(72)90177-0. [DOI] [PubMed] [Google Scholar]
- [8].Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci. 2009;29:8259–8269. doi: 10.1523/JNEUROSCI.4179-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Zeng LH, Rensing NR, Wong M T. he mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci. 2009;29:6964–6972. doi: 10.1523/JNEUROSCI.0066-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Cavazos JE, Golarai G, Sutula TP. Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. J Neurosci. 1991;11:2795–2803. doi: 10.1523/JNEUROSCI.11-09-02795.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Curia G, Longo D, Biagini G, Jones RS, Avoli M. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008;172:143–157. doi: 10.1016/j.jneumeth.2008.04.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Buckmaster PS, Dudek FE. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J Comp Neurol. 1997;385:385–404. doi: 10.1002/(SICI)1096-9861(19970901)385:3<385::AID-CNE4>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
- [13].Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci. 1985;5:1016–1022. doi: 10.1523/JNEUROSCI.05-04-01016.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Wuarin JP, Dudek FE. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats. J Neurosci. 1996;16:4438–4448. doi: 10.1523/JNEUROSCI.16-14-04438.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Molnar P, Nadler JV. Lack of effect of mossy fiber-released zinc on granule cell GABA(A) receptors in the pilocarpine model of epilepsy. J Neurophysiol. 2001;85:1932–1940. doi: 10.1152/jn.2001.85.5.1932. [DOI] [PubMed] [Google Scholar]
- [16].Lynch M, Sutula T. Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats. J Neurophysiol. 2000;83:693–704. doi: 10.1152/jn.2000.83.2.693. [DOI] [PubMed] [Google Scholar]
- [17].Sloviter RS. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann Neurol. 1994;35:640–654. doi: 10.1002/ana.410350604. [DOI] [PubMed] [Google Scholar]
- [18].Fujikawa DG. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996;725:11–22. doi: 10.1016/0006-8993(96)00203-x. [DOI] [PubMed] [Google Scholar]
- [19].Holmes GL. Seizure-induced neuronal injury: animal data. Neurology. 2002;59:S3–6. doi: 10.1212/WNL.59.9_suppl_5.S3. [DOI] [PubMed] [Google Scholar]
- [20].Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5:380–391. doi: 10.1038/nrneurol.2009.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Raol YS, Budreck EC, Brooks-Kayal AR. Epilepsy after earlylife seizures can be independent of hippocampal injury. Ann Neurol. 2003;53:503–511. doi: 10.1002/ana.10490. [DOI] [PubMed] [Google Scholar]
- [22].Dube CM, Ravizza T, Hamamura M, Zha Q, Keebaugh A, Fok K, et al. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J Neurosci. 2010;30:7484–7494. doi: 10.1523/JNEUROSCI.0551-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Baram TZ, Jensen FE, Brooks-Kayal A. Does acquired epileptogenesis in the immature brain require neuronal death. Epilepsy Curr. 2011;11:21–26. doi: 10.5698/1535-7511-11.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, Jensen FE. Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures. J Neurosci. 2008;28:7979–7990. doi: 10.1523/JNEUROSCI.1734-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Raol YH, Lund IV, Bandyopadhyay S, Zhang G, Roberts DS, Wolfe JH, et al. Enhancing GABA(A) receptor alpha 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. J Neurosci. 2006;26:11342–11346. doi: 10.1523/JNEUROSCI.3329-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Brewster A, Bender RA, Chen Y, Dube C, Eghbal-Ahmadi M, Baram TZ. Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner. J Neurosci. 2002;22:4591–4599. doi: 10.1523/JNEUROSCI.22-11-04591.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Chen K, Ratzliff A, Hilgenberg L, Gulyas A, Freund TF, Smith M, et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron. 2003;39:599–611. doi: 10.1016/S0896-6273(03)00499-9. [DOI] [PubMed] [Google Scholar]
- [28].Zeng LH, McDaniel S, Rensing NR, Wong M. Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): a double-edged sword? Cell Cycle. 2010;9:2281–2285. doi: 10.4161/cc.9.12.11866. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].McLin JP, Steward O. Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains. Eur J Neurosci. 2006;24:2191–2202. doi: 10.1111/j.1460-9568.2006.05111.x. [DOI] [PubMed] [Google Scholar]
- [30].Muller CJ, Groticke I, Bankstahl M, Loscher W. Behavioral and cognitive alterations, spontaneous seizures, and neuropathology developing after a pilocarpine-induced status epilepticus in C57BL/6 mice. Exp Neurol. 2009;219:284–297. doi: 10.1016/j.expneurol.2009.05.035. [DOI] [PubMed] [Google Scholar]
- [31].Schauwecker PE. Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus. Neurobiol Dis. 2012;45:297–304. doi: 10.1016/j.nbd.2011.08.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
