Early Aberrant Growth of Mossy Fibers after Status Epilepticus in the Immature Rat Brain

  • A. RamiEmail author
  • J. Niquet
  • A. Konoplew


Axonal sprouting is recognized to be an important mean of repair after neurologic injury. Some characteristic aftermaths of pilocarpine-induced status epilepticus (SE) in the immature rat are nerve cell loss and rearrangement of neuronal fibers. SE induced cell degeneration exclusively in the hippocampal CA1 subfield. Development of neuronal death becomes evident within hours after SE, following a delayed time course ranging from 6 to 48 h post-SE. An incidental finding is that pilocarpine induces within 48 h an aberrant growth of hippocampal mossy fibers in the hippocampus, especially in the infrapyramidal region of the CA3-subfield. We found a strong infrapyramidal band of mossy fibers along the entire stratum oriens of the CA3-region. No mossy fibers sprouting into the inner molecular layer of the dentate gyrus, or CA1 sprouting into the stratum moleculare of CA1 were noted. Signs of aberrant connectivity were found in six of the 10 pilocarpine-treated animals. This study provides the demonstration that pilocarpine within 48 h consistently results in the formation of ectopic hippocampal mossy fibers in a 2-week-old pup. This indicates a high degree of axonal reorganization in the hippocampus. It remains controversial whether such reorganization is the cause or consequence of chronic seizures. We assume that these additional infrapyramidal mossy fibers may influence the way in which granule cells drive pyramidal cells in CA3.


Status epilepticus Pilocarpine Hippocampus Mossy fibers Immature rat 



We thank Professor J. Stehle for scientific support of our work. This work was supported partly by the Adolf-Messer-Stiftung (grant to A. Rami—“Molecular mechanisms of autophagy”).


  1. 1.
    Isokawa M, Levesque MF, Babb TL, Engel JJ (1993) Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy. J Neurosci 13:1511–1522CrossRefGoogle Scholar
  2. 2.
    Thom M, Martinian L, Williams G, Stoeber K, Sisodiya SM (2005) Cell proliferation and granule cell dispersion in human hippocampal sclerosis. J Neuropathol Exp Neurol 64:194–201CrossRefGoogle Scholar
  3. 3.
    Houser CR (1990) Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res 535:195–204CrossRefGoogle Scholar
  4. 4.
    Koyama R, Ikegaya Y (2004) Mossy fiber sprouting as a potential therapeutic target for epilepsy. Curr Neurovasc Res 1:3–10CrossRefGoogle Scholar
  5. 5.
    Sloviter RS (1996) Hippocampal pathology and pathophysiology in temporal lobe epilepsy. Neurologia 4:29–32Google Scholar
  6. 6.
    Sankar R, Shin D, Wasterlain CG (2003) Development of temporal lobe epilepsy in 21-day-old rats. Epilepsia 44:872–873CrossRefGoogle Scholar
  7. 7.
    Represa A, Jorquera I, Le Gal La Salle G, Ben-Ari Y (1993) Epilepsy induced collateral sprouting of hippocampal mossy fibers: does it induce the development of ectopic synapses with granule cell dendrites?. Hippocampus 3:257–268CrossRefGoogle Scholar
  8. 8.
    Sankar R, Shin D, Liu H, Wasterlain C, Mazarati A (2002) Epileptogenesis during development: injury, circuit recruitment, and plasticity. Epilepsia 43(Suppl 5):47–53CrossRefGoogle Scholar
  9. 9.
    Sankar R, Shin DH, Liu H, Mazarati A, Pereira de Vasconcelos A, Wasterlain CG (1998) Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci 18:8382–8393CrossRefGoogle Scholar
  10. 10.
    Bagri A, Cheng HJ, Yaron A, Pleasure SJ, Tessier-Lavigne M (2003) Stereotyped pruning of long hippocampal axon branches triggered by retraction inducers of the semaphorin family. Cell 11:285–299CrossRefGoogle Scholar
  11. 11.
    Baimbridge KG, Miller JJ (1982) Immunohistochemical localization of calcium-binding protein in the cerebellum, hippocampal formation and olfactory bulb of the rat. Brain Res 245:223–229CrossRefGoogle Scholar
  12. 12.
    Amaral DG, Dent JA (1981) Development of the mossy fibers of the dentate gyrus: I. a light and electron microscopic study of the mossy fibers and their expansions. J Comp Neurol 195:51–86CrossRefGoogle Scholar
  13. 13.
    Holmes GL, Sarkisian M, Ben-Ari Y, Chevassus-Au-Louis N (1999) Mossy fiber sprouting after recurrent seizures during early development in rats. J Comp Neurol 404:537–553CrossRefGoogle Scholar
  14. 14.
    Cilio MR, Sogawa Y, Cha BH, Liu X, Huang LT, Holmes GL (2003) Long-term effects of status epilepticus in the immature brain are specific for age and model. Epilepsia 44:518–528CrossRefGoogle Scholar
  15. 15.
    Wasterlain CG (1997) Recurrent seizures in the developing brain are harmful. Epilepsia 38:728–734CrossRefGoogle Scholar
  16. 16.
    Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, Schinder AF (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11:901–907CrossRefGoogle Scholar
  17. 17.
    Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3–11CrossRefGoogle Scholar
  18. 18.
    Ribak CE, Shapiro LA, Yan XX, Dashtipour K, Nadler JV, Obenaus A, Spigelman I, Buckmaster PS (2012) Seizure-induced formation of basal dendrites on granule cells of the rodent dentate gyrus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US).CrossRefGoogle Scholar
  19. 19.
    Häussler U, Rinas K, Kilias A, Egert U, Haas CA (2016) Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy. Hippocampus 26:577–588CrossRefGoogle Scholar
  20. 20.
    Römer B, Krebs J, Overall RW, Fabel K, Babu H, Overstreet-Wadiche L, Brandt MD, Williams RW et al (2011) Adult hippocampal neurogenesis and plasticity in the infrapyramidal bundle of the mossy fiber projection: I. co-regulation by activity. Front Neurosci 27(5):107Google Scholar
  21. 21.
    Schwegler H, Crusio WE, Brust I (1990) Hippocampal mossy fibers and radial-maze learning in the mouse: a correlation with spatial working memory but not with non-spatial reference memory. Neuroscience 34:293–298CrossRefGoogle Scholar
  22. 22.
    Krebs J, Römer B, Overall RW, Fabel K, Babu H, Brandt MD, Williams RW, Jessberger S, Kempermann G (2011) Adult Hippocampal Neurogenesis and Plasticity in the Infrapyramidal Bundle of the Mossy Fiber Projection: II. Genetic Covariation and Identification of Nos1 as Linking Candidate Gene. Front Neurosci 21;5:106Google Scholar
  23. 23.
    Hartmann D, Frotscher M, Sievers J (1994) Development of granule cells, and afferent and efferent connections of the dentate gyrus after experimentally induced reorganization of the supra- and infrapyramidal blades. Acta Anat (Basel) 150:25–37CrossRefGoogle Scholar
  24. 24.
    Laurberg S, Zimmer J (1980) Aberrant hippocampal mossy fibers in cats. Brain Res 28;188:555–559CrossRefGoogle Scholar
  25. 25.
    Cheema SS, Lauder JM (1983) Infrapyramidal mossy fibers in the hippocampus of methylazoxymethanol acetate-induced microcephalic rats. Brain Res 285:411–415CrossRefGoogle Scholar
  26. 26.
    Van der Zee CE, Rashid K, Le K, Moore KA, Stanisz J, Diamond J, Racine RJ, Fahnestock M (1995) Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J Neurosci 15:5316–5323CrossRefGoogle Scholar
  27. 27.
    Laurberg S, Zimmer J (1980) Lesion-induced rerouting of hippocompal mossy fibers in developing but not in adult rats. J Comp Neurol 190(4):627–650CrossRefGoogle Scholar
  28. 28.
    Rami A, Lomri N, Bréhier A, Thomasset M, Rabié A (1989) Effects of altered thyroid states and undernutrition on the calbindin-D28K (calcium-binding protein) content of the hippocampal formation in the developing rat. Brain Res 485:20–28CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Institut für Zelluläre und Molekulare Anatomie (Anatomie III)Klinikum der Johann Wolfgang von Goethe-UniversitätFrankfurt/MainGermany
  2. 2.Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesUSA

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