Does Mossy Fiber Sprouting Give Rise to the Epileptic State?

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 813)


Many patients with temporal lobe epilepsy display structural changes in the seizure initiating zone, which includes the hippocampus. Structural changes in the hippocampus include granule cell axon (mossy fiber) sprouting. The role of mossy fiber sprouting in epileptogenesis is controversial. A popular view of temporal lobe epileptogenesis contends that precipitating brain insults trigger transient cascades of molecular and cellular events that permanently enhance excitability of neuronal networks through mechanisms including mossy fiber sprouting. However, recent evidence suggests there is no critical period for mossy fiber sprouting after an epileptogenic brain injury. Instead, findings from stereological electron microscopy and rapamycin-delayed mossy fiber sprouting in rodent models of temporal lobe epilepsy suggest a persistent, homeostatic mechanism exists to maintain a set level of excitatory synaptic input to granule cells. If so, a target level of mossy fiber sprouting might be determined shortly after a brain injury and then remain constant. Despite the static appearance of synaptic reorganization after its development, work by other investigators suggests there might be continual turnover of sprouted mossy fibers in epileptic patients and animal models. If so, there may be opportunities to reverse established mossy fiber sprouting. However, reversal of mossy fiber sprouting is unlikely to be antiepileptogenic, because blocking its development does not reduce seizure frequency in pilocarpine-treated mice. The challenge remains to identify which, if any, of the many other structural changes in the hippocampus are epileptogenic.


Dentate gyrus Granule cell Epilepsy Epileptogenesis Hilus Seizure Pilocarpine 



Dedicated to Philip A. Schwartzkroin, a trusted graduate advisor and outstanding research mentor who taught me so much over the years.

Other Acknowledgements

Supported by NINDS/NIH.


  1. 1.
    Babb TL, Pretorius JK, Kupfer WR, Crandall PH (1989) Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J Neurosci 9:2562–2574PubMedGoogle Scholar
  2. 2.
    Buckmaster PS (2012) Mossy fiber sprouting in the dentate gyrus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Japser’s basic mechanisms of the epilepsies, 4th edn. Oxford University Press, New York, pp 416–431CrossRefGoogle Scholar
  3. 3.
    Buckmaster PS, Ingram EA, Wen X (2009) 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 29:8259–8269PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Buckmaster PS, Jongen-Rêlo AL (1999) Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats. J Neurosci 19:9519–9529PubMedGoogle Scholar
  5. 5.
    Buckmaster PS, Lew FH (2011) Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 31:2337–2347PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Buckmaster PS, Strowbridge BW, Kunkel DD, Schmiege DL, Schwartzkroin PA (1992) Mossy cell axonal projections to the dentate gyrus molecular layer in the rat hippocampal slice. Hippocampus 2:349–362PubMedCrossRefGoogle Scholar
  7. 7.
    Buckmaster PS, Wen X (2011) Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy. Epilepsia 52:2057–2064PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Buckmaster PS, Wenzel HJ, Kunkel DD, Schwartzkroin PA (1996) Axon arbors and synaptic connections of hippocampal mossy cells in the rat in vivo. J Comp Neurol 366:270–292CrossRefGoogle Scholar
  9. 9.
    Buckmaster PS, Zhang G, Yamawaki R (2002) Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J Neurosci 22:6650–6658PubMedGoogle Scholar
  10. 10.
    Davis GW, Goodman CS (1998) Genetic analysis of synaptic development and plasticity: homeostatic regulation of synaptic efficacy. Curr Opin Neurobiol 8:149–156PubMedCrossRefGoogle Scholar
  11. 11.
    de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD (1989) Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res 495:387–395PubMedCrossRefGoogle Scholar
  12. 12.
    Engel J Jr, Williamson PD, Wieser H-G (1997) Mesial temporal lobe epilepsy. In: Engel J Jr, Pedley TA (eds) Epilepsy: a comprehensive textbook. Lippincott-Raven, Philadelphia, pp 2417–2426Google Scholar
  13. 13.
    Franck JE, Pokorny J, Kunkel DD, Schwartzkroin PA (1995) Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia 36:543–558PubMedCrossRefGoogle Scholar
  14. 14.
    Ganeshina O, Berry RW, Petralia RS, Nicholson DA, Geinesman Y (2004) Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities. J Comp Neurol 468:86–95PubMedCrossRefGoogle Scholar
  15. 15.
    Gloor P (1997) The temporal lobe and limbic system. Oxford University Press, New York, pp 677–691Google Scholar
  16. 16.
    Gunderson VM, Dubach M, Szot P, Born DE, Wenzel JH, Maravilla KR, Zierath DK, Robbins CA, Schwartzkroin PA (1999) Development of a model of status epilepticus in pigtailed macaque infant monkeys. Dev Neurosci 21:352–364PubMedCrossRefGoogle Scholar
  17. 17.
    Hattiangady B, Rao MS, Shetty AK (2004) Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis 17:473–490PubMedCrossRefGoogle Scholar
  18. 18.
    Heng K, Haney MM, Buckmaster PS (2013) High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia 54:1535–1541PubMedCrossRefGoogle Scholar
  19. 19.
    Houser CR (1990) Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res 535:195–204PubMedCrossRefGoogle Scholar
  20. 20.
    Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y (2010) Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 40:193–199PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Isokawa M, Levesque MF, Babb TL, Engel JE Jr (1993) Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy. J Neurosci 13:1511–1522PubMedGoogle Scholar
  22. 22.
    Jessberger S, Zhao C, Toni N, Clemenson GD Jr, Li Y, Gage FH (2007) Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci 27:9400–9407PubMedCrossRefGoogle Scholar
  23. 23.
    Jiao Y, Nadler JV (2007) Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting. Exp Neurol 205:569–582PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Jinde S, Zsiros V, Jiang Z, Nakao K, Pickel J, Kohno K, Belforte JE, Nakazawa K (2012) Hilar mossy cell degeneration causes transient dentate granule cell hyperexcitability and impaired pattern separation. Neuron 76:1189–1200PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Kron MM, Zhang H, Parent JM (2010) The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci 30:2051–2059PubMedCrossRefGoogle Scholar
  26. 26.
    Kumar SS, Buckmaster PS (2006) Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 26:4613–4623PubMedCrossRefGoogle Scholar
  27. 27.
    Lew F, Buckmaster PS (2011) Is there a critical period for mossy fiber sprouting in a mouse model of temporal lobe epilepsy? Epilepsia 52:2326–2332PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Maglóczky Z, Wittner L, Borhegyi Z, Halász P, Vajda J, Czirják S, Freund TF (2000) Changes in the distribution and connectivity of interneurons in the epileptic human dentate gyrus. Neuroscience 96:7–25PubMedCrossRefGoogle Scholar
  29. 29.
    Margerison JH, Corsellis JAN (1966) Epilepsy and the temporal lobes. Brain 89:499–530PubMedCrossRefGoogle Scholar
  30. 30.
    Mathern GW, Pretorius JK, Babb TL (1995) Influence of the type of initial precipitating injury and at what age it occurs on course and outcome in patients with temporal lobe seizures. J Neurosurg 82:220–227PubMedCrossRefGoogle Scholar
  31. 31.
    McKhann GM 2nd, Wenzel HJ, Robbins CA, Sosunov AA, Schwartzkroin PA (2003) Mouse strain differences in kainic acid sensitivity, seizure behavior, mortality, and hippocampal pathology. Neuroscience 122:551–561PubMedCrossRefGoogle Scholar
  32. 32.
    Mikkonen M, Soininen H, Kälviäinen R, Tapiola T, Ylinen A, Vapalahti M, Paljärvi L, Pitkänen A (1998) Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecular in the hippocampus and entorhinal cortex. Ann Neurol 44:923–934PubMedCrossRefGoogle Scholar
  33. 33.
    Murthy VN, Schikorski T, Stevens CF, Zhu Y (2001) Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32:673–682PubMedCrossRefGoogle Scholar
  34. 34.
    Nadler JV, Perry BW, Cotman CW (1980) Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid. Brain Res 182:1–9Google Scholar
  35. 35.
    Nusser Z, Lujan R, Laube G, Roberts JDB, Molnar E, Somogyi P (1998) Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21:545–559PubMedCrossRefGoogle Scholar
  36. 36.
    Proper EA, Oestreicher AB, Jansen GH, Veelen CWM, van Rijen PC, Gispen WH, de Graan PNE (2000) Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 123:19–30PubMedCrossRefGoogle Scholar
  37. 37.
    Quesney LF (1986) Clinical and EEG features of complex partial seizures of temporal lobe origin. Epilepsia 27(Suppl 2):S27–S45PubMedCrossRefGoogle Scholar
  38. 38.
    Rakhade SN, Jensen FE (2009) Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol 5:380–391PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Scharfman HE, Schwartzkroin PA (1988) Electrophysiology of morphologically identified mossy cells of the dentate hilus recorded in guinea pig hippocampal slices. J Neurosci 8:3812–3821PubMedGoogle Scholar
  40. 40.
    Schwartzkroin PA (1994) Role of the hippocampus in epilepsy. Hippocampus 4:239–242PubMedCrossRefGoogle Scholar
  41. 41.
    Schwartzkroin PA (1997) Origins of the epileptic state. Epilepsia 38:853–858PubMedCrossRefGoogle Scholar
  42. 42.
    Shetty AK, Zaman V, Hattiangady B (2005) Repair of the injured adult hippocampus through graft-mediated modulation of the plasticity of the dentate gyrus in a rat model of temporal lobe epilepsy. J Neurosci 25:8391–8401PubMedCrossRefGoogle Scholar
  43. 43.
    Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K (2012) Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci Lett 509:105–109PubMedCrossRefGoogle Scholar
  44. 44.
    Sloviter RS (1992) Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats. Neurosci Lett 137:91–96PubMedCrossRefGoogle Scholar
  45. 45.
    Spencer SS, Williamson PD, Spencer DD, Mattson RH (1987) Human hippocampal seizure spread studied by depth and subdural recording: the hippocampal commissure. Epilepsia 28:479–489PubMedCrossRefGoogle Scholar
  46. 46.
    Steward O (1976) Reinnervation of dentate gyrus by homologous afferents following entorhinal cortical lesions in adult rats. Science 194:426–428PubMedCrossRefGoogle Scholar
  47. 47.
    Swiech L, Perycz M, Malik A, Jaworski J (2008) Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta 1784:116–132PubMedCrossRefGoogle Scholar
  48. 48.
    Tauck DL, Nadler JV (1985) Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci 5:1016–1022PubMedGoogle Scholar
  49. 49.
    Thind KK, Yamawaki R, Phanwar I, Zhang G, Wen X, Buckmaster PS (2010) Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy. J Comp Neurol 518:647–667PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Turrigiano GG (2008) The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135:422–435PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Vaidya VA, Siuciak JA, Du F, Duman RS (1999) Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience 89:157–166PubMedCrossRefGoogle Scholar
  52. 52.
    van Vliet EA, Forte G, Holtman L, den Buerger JCG, Sinjewel A, de Vries HE, Aronica E, Gorter JA (2012) Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia 43:1254–1263CrossRefGoogle Scholar
  53. 53.
    von Campe G, Spencer DD, de Lanerolle NC (1997) Morphology of dentate granule cells in the human hippocampus. Hippocampus 7:472–488CrossRefGoogle Scholar
  54. 54.
    Wenzel HJ, Buckmaster PS, Anderson NL, Wenzel ME, Schwartzkroin PA (1997) Ultrastructural localization of neurotransmitter immunoreactivity in mossy cell axons and their synaptic targets in the rat dentate gyrus. Hippocampus 7:559–570PubMedCrossRefGoogle Scholar
  55. 55.
    Wenzel HJ, Cole TB, Born DE, Schwartzkroin PA, Palmiter RD (1997) Ultrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. Proc Natl Acad Sci U S A 94:12676–12681PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Wenzel HJ, Born DE, Dubach MF, Gunderson VM, Maravilla KR, Robbins CA, Szot P, Zierath D, Schwartzkroin PA (2000) Morphological plasticity in an infant monkey model of temporal lobe epilepsy. Epilepsia 41(Suppl 6):S70–S75CrossRefGoogle Scholar
  57. 57.
    Wenzel HJ, Robbins CA, Tsai LH, Schwartzkroin PA (2001) Abnormal morphological and functional organization of the hippocampus in a p35 mutant model of cortical dysplasia with spontaneous seizures. J Neurosci 21:983–998PubMedGoogle Scholar
  58. 58.
    Wenzel HJ, Woolley CS, Robbins CA, Schwartzkroin PA (2000) Kainic acid-induced mossy fiber sprouting and synapse formation in the dentate gyrus of rats. Hippocampus 10:244–260PubMedCrossRefGoogle Scholar
  59. 59.
    Zeng L-H, Rensing NR, Wong M (2009) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 29:6964–6972PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Zhang W, Huguenard JR, Buckmaster PS (2012) Increased positive-feedback from hilar and CA3 neurons to granule cells in a rat model of temporal lobe epilepsy. J Neurosci 32:1183–1196PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Departments of Comparative Medicine and Neurology & Neurological SciencesStanford UniversityStanfordUSA

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