Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2008 Feb 1;23(2):83–91. doi: 10.1007/s12264-007-0012-3

Morphological and behavioral consequences of recurrent seizures in neonatal rats are associated with glucocorticoid levels

新生期大鼠反复痫性发作的形态学及行为学结果与糖皮质激素水平升高有关

Xiu-Yu Shi 1, Ji-Wen Wang 1, Ge-Fei Lei 1, Ruo-Peng Sun 1,✉
PMCID: PMC5550591  PMID: 17592530

Abstract

Objective

It is well documented that epilepsy can increase neurogenesis in certain brain regions and cause behavioral alternations in patients and different epileptic animal models. A series of experimental studies have demonstrated that neurogenesis is regulated by various factors including glucocorticoid (CORT), which can reduce neurogenesis. Most of studies in animal have been focused on adulthood stage, while the effect of recurrent seizures to immature brain in neonatal period has not been well established. This study was designed to investigate how the recurrent seizures occurred in the neonatal period affected the immature brain and how CORT regulated neurogenesis in immature animals.

Methods

Neonatal rats were subjected to 3 pilocarpine-induced seizures from postnatal day 1 to day 7. Then neurogenesis at different postnatal ages (i.e. P8, P12, P22, P50) was observed. Behavioral performance was tested when the rats were mature (P40), and plasma CORT levels following recurrent seizures were simultaneously monitored.

Results

Rats with neonatal seizures had a significant reduction in the number of Bromodeoxyuridine (BrdU) labeled cells in the dentate gyrus compared with the control groups when the animals were euthanized on P8 or P12 (P < 0.05); whereas there was no difference between the two groups on P22. Until P50, rats with neonatal seizures had increased number of BrdU-labeled cells compared with the control group (P < 0.05). In Morris water maze task, pilocarpine-treated rats were significantly slower than the control rats at the first and second day, and there were no differences at other days. In probe trial, there was no significant difference in time spent in the goal quadrant between the two groups. Endocrine studies showed a correlation between the number of BrdU positive cells and the CORT level. Sustained increase in circulating CORT levels was observed following neonatal seizures on P8 and P12.

Conclusion

Neonatal recurrent seizures can biphasely modulate neurogenesis over different time windows with a down-regulation at early time and up-regulation afterwards, cause persistent deficits in cognitive functions of adults, and increase the circulating CORT levels. CORT levels are related with the morphological and behavioral consequences of recurrent seizures.

Keywords: epilepsy, development, cell proliferation, learning, memory, glucocorticoid

References

  • [1].Painter M.J., Bergman I., Crumrine P. Neonatal seizures. Pediatr Clin North Am. 1986;33:91–109. doi: 10.1016/s0031-3955(16)34971-9. [DOI] [PubMed] [Google Scholar]
  • [2].Parent J.M., Yu T.W., Leibowitz R.T., Geschwind D.H., Sloviter R.S., Lowenstein D.H. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 1997;17:3727–3738. doi: 10.1523/JNEUROSCI.17-10-03727.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Gray W.P., Sundstrom L.E. Kainic acid increases the proliferation of granule cell progenitor in the dentate gyrus of the adult rat. Brain Res. 1998;790:52–59. doi: 10.1016/S0006-8993(98)00030-4. [DOI] [PubMed] [Google Scholar]
  • [4].Scott B.W., Wang S., Burnham W.M., De Boni U., Wojtowicz J.M. Kindling-induced neurogenesis in the dentate gyrus of the rat. Neurosci Lett. 1998;248:73–76. doi: 10.1016/S0304-3940(98)00355-3. [DOI] [PubMed] [Google Scholar]
  • [5].Sankar R., Shin D., Liu H., Katsumori H., Wasterlain C.G. Granule cell neurogenesis after status epilepticus in the immature rat brain. Epilepsia. 2000;41(Suppl6):S53–S56. doi: 10.1111/j.1528-1157.2000.tb01557.x. [DOI] [PubMed] [Google Scholar]
  • [6].Wang Y.L., Sun R.P., Lei G.F., Wang J.W., Guo S.H. Neurogenesis of dentate granule cells following kainic acid induced seizures in immature rats. Zhonghua Er Ke Za Zhi. 2004;42:621–624. [PubMed] [Google Scholar]
  • [7].McCabe B.K., Silveira D.C., Cilio M.R., Cha B.H., Liu X., Sogawa Y., et al. Reduced neurogenesis after neonatal seizures. J Neurosci. 2001;21:2094–2103. doi: 10.1523/JNEUROSCI.21-06-02094.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Mathern G.W., Leiphart J.L., De Vera A., Adelson P.D., Seki T., Neder L., et al. Seizures decrease postnatal neurogenesis and granule cell development in the human fascia dentata. Epilepsia. 2002;43(Suppl5):68–73. doi: 10.1046/j.1528-1157.43.s.5.28.x. [DOI] [PubMed] [Google Scholar]
  • [9].Altman J., Das G.D. Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol. 1966;126:337–389. doi: 10.1002/cne.901260302. [DOI] [PubMed] [Google Scholar]
  • [10].Cameron H.A., Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience. 1994;61:203–209. doi: 10.1016/0306-4522(94)90224-0. [DOI] [PubMed] [Google Scholar]
  • [11].Corotto F.S., Henegar J.A., Maruniak J.A. Neurogenesis persists in the subependymal layer of the adult mouse brain. Neurosci Lett. 1993;149:111–114. doi: 10.1016/0304-3940(93)90748-A. [DOI] [PubMed] [Google Scholar]
  • [12].Izquierdo I., Medina J.H. Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem. 1997;68:285–316. doi: 10.1006/nlme.1997.3799. [DOI] [PubMed] [Google Scholar]
  • [13].Kempermann G. Why new neurons? Possible functions for adult hippocampal neurogenesis. J Neurosci. 2002;22:635–638. doi: 10.1523/JNEUROSCI.22-03-00635.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Parent J.M., Elliott R.C., Pleasure S.J., Barbaro N.M., Lowenstein D.H. Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol. 2006;59:81–91. doi: 10.1002/ana.20699. [DOI] [PubMed] [Google Scholar]
  • [15].Cheng L., Gong S., Shan L.D., Xu W.P., Zhang Y.L., Guo S.Y., et al. Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats. Neurosci Bull. 2006;22:1–6. [PubMed] [Google Scholar]
  • [16].Haughey N.J., Nath A., Chan S.L., Borchard A.C., Rao M.S., Mattson M.P. Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem. 2002;83:1509–1524. doi: 10.1046/j.1471-4159.2002.01267.x. [DOI] [PubMed] [Google Scholar]
  • [17].Nixon K., Crews F.T. Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J Neurochem. 2002;83:1087–1093. doi: 10.1046/j.1471-4159.2002.01214.x. [DOI] [PubMed] [Google Scholar]
  • [18].Pham K., Nacher J., Hof P.R., McEwen B.S. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci. 2003;17:879–886. doi: 10.1046/j.1460-9568.2003.02513.x. [DOI] [PubMed] [Google Scholar]
  • [19].Bayer S.A. Quantitative 3H-thymidine radiographic analyses of neurogenesis in rat amygdala. J Comp Neurosci. 1980;194:845–875. doi: 10.1002/cne.901940409. [DOI] [PubMed] [Google Scholar]
  • [20].Gould E., Woolley C.S., Cameron H.A., Daniels D.C., McEwen B.S. Adrenal steroids regulate postnatal development of the rat den tate gyrus: II, effects of glucocort icoids and ineralocorticoids on cell birth. J Comp Neurol. 1991;313:486–493. doi: 10.1002/cne.903130309. [DOI] [PubMed] [Google Scholar]
  • [21].Lado F.A., Sperber E.F., Moshe S.L. Anticonvulsant efficacy of gabapentin on kindling in the immature brain. Epilepsia. 2001;42:458–463. doi: 10.1046/j.1528-1157.2001.30900.x. [DOI] [PubMed] [Google Scholar]
  • [22].Cavalheiro E.A., Leite J.P., Bortolotto Z.A., Turski W.A., Ikonomidou C., Turski L. Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia. 1991;32:778–782. doi: 10.1111/j.1528-1157.1991.tb05533.x. [DOI] [PubMed] [Google Scholar]
  • [23].Mehler M.F., Kessler J.A. Progenitor cell biology. Implications for neural regeneration. Arch Neurol. 1999;56:780–784. doi: 10.1001/archneur.56.7.780. [DOI] [PubMed] [Google Scholar]
  • [24].Young D., Lawlor P.A., Leone P., Dragunow M., During M.J. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med. 1999;5:448–453. doi: 10.1038/7449. [DOI] [PubMed] [Google Scholar]
  • [25].Shi X.Y., Wang J.W., Sun R.P. Effects and consequences of recurrent seizures of neonatal rat on the hippocampal neurogenesis (in Chinese) Zhonghua Er Ke Za Zhi. 2006;44:289–293. [PubMed] [Google Scholar]
  • [26].Cameron H.A., McKay R.D. Restoring production of hippocampal neurons in old age. Nat Neurosci. 1999;2:894–897. doi: 10.1038/13197. [DOI] [PubMed] [Google Scholar]
  • [27].Gould E., Cameron H.A., McEwen B.S. Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol. 1994;340:551–556. doi: 10.1002/cne.903400408. [DOI] [PubMed] [Google Scholar]
  • [28].Kee N.J., Preston E., Wojtowicz J.M. Enhanced neurogenesis after transient global ischemia in the dentate gyrus. Exp Brain Res. 2001;136:313–320. doi: 10.1007/s002210000591. [DOI] [PubMed] [Google Scholar]
  • [29].Kornblum H.I., Sankar R., Shin D.H., Wasterlain C.G., Gall C.M. Induced of brain derived neurotrophic factor mRNA by seizures induced neonatal and juvenile rat brain. Brain Res Mol Brain Res. 1997;44:219–228. doi: 10.1016/S0169-328X(96)00224-0. [DOI] [PubMed] [Google Scholar]
  • [30].Coburn-Litvak P.S., Pothakos K., Tata D.A., McCloskey D.P., Anderson B.J. Chronic administration of corticosterone impairs spatial reference memory before spatial working memory in rats. Neurobiol Learn Mem. 2003;80:11–23. doi: 10.1016/S1074-7427(03)00019-4. [DOI] [PubMed] [Google Scholar]
  • [31].Woodson J.C., Macintosh D., Fleshner M., Diamond D.M. Emotioninduced amnesia in rats: working memory-specific impairment, corticosterone-memory correlation, and fear versus arousal effects on memory. Learn Mem. 2003;10:326–336. doi: 10.1101/lm.62903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Wong E.Y., Herbert J. Glucocorticoids environment: a determining factor for neural progenitors survival in the adult hippocampus. Eur J Neurosci. 2004;20:2491–2498. doi: 10.1111/j.1460-9568.2004.03717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Wong E.Y., Herbert J. Raised circulating corticosterone inhibits neuronal differentiation of progenitor cells in the adult hippocampus. Neuroscience. 2006;137:83–92. doi: 10.1016/j.neuroscience.2005.08.073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Shors T.J., Miesegaes G., Beylin A., Zhao M., Rydel T., Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001;410:372–376. doi: 10.1038/35066584. [DOI] [PubMed] [Google Scholar]
  • [35].Watanabe Y., Gould E., McEwen B.S. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341–345. doi: 10.1016/0006-8993(92)91597-8. [DOI] [PubMed] [Google Scholar]
  • [36].Magarinos A.M., McEwen B.S. Stress-induced atrophy of apical dendrites of hippocampal CA3 neurons: comparison of stressors. Neuroscience. 1995;69:83–88. doi: 10.1016/0306-4522(95)00256-I. [DOI] [PubMed] [Google Scholar]
  • [37].Zhang L., Zhao Z.X. The impact of synapsins on synaptic plasticity and cognitive behaviours. Neurosci Bull. 2006;22:63–67. [PubMed] [Google Scholar]
  • [38].Brunson K.L., Baram T.Z., Bender R.A. Hippocampal neurogenesis is not enhanced by lifelong reduction of glucocorticoid levels. Hippocampus. 2005;15:491–501. doi: 10.1002/hipo.20074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Vazquez D.M. Stress and the developing limbic-hypothalamicpituitary-adrenal axis. Psychoneuroendocrinology. 1998;23:663–700. doi: 10.1016/S0306-4530(98)00029-8. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES