Experimental Brain Research

, Volume 200, Issue 2, pp 141–149 | Cite as

Reelin deficiency causes granule cell dispersion in epilepsy

  • Carola A. HaasEmail author
  • Michael Frotscher


Cortical migration defects are often associated with epilepsy. In mesial temporal lobe epilepsy (MTLE), granule cell dispersion (GCD), a migration defect of dentate granule cells, is frequently observed. Little is known how GCD develops and to which extent it contributes to the development of seizure activity. Since the reelin-deficient reeler mouse mutant shows a similar migration defect of dentate cells, we performed a series of studies investigating whether reelin deficiency is involved in GCD development. We show that in MTLE patients and in a mouse model of MTLE, the development of GCD correlates with a loss of the extracellular matrix protein reelin. In addition, we present evidence that GCD occurs in the absence of neurogenesis, thus representing a displacement of mature neurons due to a reelin deficiency. Accordingly, antibody blockade of reelin function in naïve, adult mice induced GCD. Finally, we show that GCD formation can be prevented by infusion of exogenous reelin. In summary, these studies show that in epilepsy reelin dysfunction causes GCD development and that reelin is important for the maintenance of layered structures in the adult brain.


Hippocampus Neuronal migration Neurogenesis Dentate gyrus Seizure Mouse 



The authors thank all those who contributed with their time and talents to the studies reviewed in this article. In particular, we thank M. Müller, M. Osswald, C. Heinrich, U. Häussler, A. Jacobi, A. Fahrner, E. Förster, and S. Huber for their contributions. This work was supported by the Deutsche Forschungsgemeinschaft (SFB TR 3).


  1. Armstrong DD (1993) The neuropathology of temporal lobe epilepsy. J Neuropathol Exp Neurol 52:433–443CrossRefPubMedGoogle Scholar
  2. Blümcke I, Schewe JC, Normann S, Brustle O, Schramm J, Elger CE, Wiestler OD (2001) Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus 11:311–321CrossRefPubMedGoogle Scholar
  3. Blümcke I, Thom M, Wiestler OD (2002) Ammon’s horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy. Brain Pathol 12:199–211PubMedGoogle Scholar
  4. Bouilleret V, Ridoux V, Depaulis A, Marescaux C, Nehlig A, Le Gal La Salle G (1999) Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience 89:717–729CrossRefPubMedGoogle Scholar
  5. Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG (2003) Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467:1–10CrossRefPubMedGoogle Scholar
  6. Chai X, Förster E, Zhao S, Bock HH, Frotscher M (2009) Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3. J Neurosci 29:288–299CrossRefPubMedGoogle Scholar
  7. Cooper JA (2008) A mechanism for inside-out lamination in the neocortex. Trends Neurosci 31:113–119CrossRefPubMedGoogle Scholar
  8. Crespel A, Rigau V, Coubes P, Rousset MC, de Bock F, Okano H, Baldy-Moulinier M, Bockaert J, Lerner-Natoli M (2005) Increased number of neural progenitors in human temporal lobe epilepsy. Neurobiol Dis 19:436–450CrossRefPubMedGoogle Scholar
  9. D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723CrossRefPubMedGoogle Scholar
  10. D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T (1999) Reelin is a ligand for lipoprotein receptors. Neuron 24:471–479CrossRefPubMedGoogle Scholar
  11. des Portes V, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrie A, Gelot A, Dupuis E, Motte J, Berwald-Netter Y, Catala M, Kahn A, Beldjord C, Chelly J (1998) A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92:51–61CrossRefPubMedGoogle Scholar
  12. Drakew A, Deller T, Heimrich B, Gebhardt C, Del Turco D, Tielsch A, Förster E, Herz J, Frotscher M (2002) Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice. Exp Neurol 176:12–24CrossRefPubMedGoogle Scholar
  13. Eksioglu YZ, Scheffer IE, Cardenas P, Knoll J, DiMario F, Ramsby G, Berg M, Kamuro K, Berkovic SF, Duyk GM, Parisi J, Huttenlocher PR, Walsh CA (1996) Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 16:77–87CrossRefPubMedGoogle Scholar
  14. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317CrossRefPubMedGoogle Scholar
  15. Fahrner A, Kann G, Flubacher A, Heinrich C, Freiman TM, Zentner J, Frotscher M, Haas CA (2007) Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol 203:320–332CrossRefPubMedGoogle Scholar
  16. Falconer DS (1951) Two new mutants, Trembler and Reeler, with neurological actions in the house mouse. J Genet 50:192–201CrossRefGoogle Scholar
  17. Fauser S, Schulze-Bonhage A (2006) Epileptogenicity of cortical dysplasia in temporal lobe dual pathology: an electrophysiological study with invasive recordings. Brain 129:82–95CrossRefPubMedGoogle Scholar
  18. Förster E, Zhao S, Frotscher M (2006) Laminating the hippocampus. Nat Rev Neurosci 7:259–267CrossRefPubMedGoogle Scholar
  19. Frotscher M (1998) Cajal-Retzius cells, Reelin, and the formation of layers. Curr Opin Neurobiol 8:570–575CrossRefPubMedGoogle Scholar
  20. Frotscher M, Haas C, Förster E (2003) Reelin controls granule cell migration in the dentate gyrus by acting on the radial glia scaffold. Cereb Cortex 13:634–640CrossRefPubMedGoogle Scholar
  21. Gleeson JG, Walsh CA (2000) Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci 23:352–359CrossRefPubMedGoogle Scholar
  22. Gray WP, Sundstrom LE (1998) Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790:52–59CrossRefPubMedGoogle Scholar
  23. Haas CA, Dudeck O, Kirsch M, Huszka C, Kann G, Pollak S, Zentner J, Frotscher M (2002) Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neurosci 22:5797–5802PubMedGoogle Scholar
  24. Heinrich C, Nitta N, Flubacher A, Muller M, Fahrner A, Kirsch M, Freiman T, Suzuki F, Depaulis A, Frotscher M, Haas CA (2006) Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci 26:4701–4713CrossRefPubMedGoogle Scholar
  25. Hirotsune S, Takahara T, Sasaki N, Hirose K, Yoshiki A, Ohashi T, Kusakabe M, Murakami Y, Muramatsu M, Watanabe S, Nakao K, Katsuki M, Hayashizaki Y (1995) The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons. Nat Genet 10:77–83CrossRefPubMedGoogle Scholar
  26. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93–96CrossRefPubMedGoogle Scholar
  27. Houser CR (1990) Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res 535:195–204CrossRefPubMedGoogle Scholar
  28. Howell BW, Hawkes R, Soriano P, Cooper JA (1997) Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389:733–737CrossRefPubMedGoogle Scholar
  29. Howell BW, Herrick TM, Cooper JA (1999) Reelin-induced tryosine phosphorylation of disabled 1 during neuronal positioning. Genes Dev 13:643–648CrossRefPubMedGoogle Scholar
  30. Jessberger S, Romer B, Babu H, Kempermann G (2005) Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp Neurol 196:342–351CrossRefPubMedGoogle Scholar
  31. Katsuyama Y, Terashima T (2009) Developmental anatomy of reeler mutant mouse. Dev Growth Differ 51:271–286PubMedCrossRefGoogle Scholar
  32. Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447–452CrossRefPubMedGoogle Scholar
  33. Kralic JE, Ledergerber DA, Fritschy JM (2005) Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures. Eur J Neurosci 22:1916–1927CrossRefPubMedGoogle Scholar
  34. Lurton D, Sundstrom L, Brana C, Bloch B, Rougier A (1997) Possible mechanisms inducing granule cell dispersion in humans with temporal lobe epilepsy. Epilepsy Res 26:351–361CrossRefPubMedGoogle Scholar
  35. Mathern GW, Leiphart JL, De Vera A, Adelson PD, Seki T, Neder L, Leite JP (2002) Seizures decrease postnatal neurogenesis and granule cell development in the human fascia dentata. Epilepsia 43(Suppl 5):68–73CrossRefPubMedGoogle Scholar
  36. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250CrossRefPubMedGoogle Scholar
  37. Müller MC, Osswald M, Tinnes S, Haussler U, Jacobi A, Förster E, Frotscher M, Haas CA (2009) Exogenous reelin prevents granule cell dispersion in experimental epilepsy. Exp Neurol 216:390–397CrossRefPubMedGoogle Scholar
  38. Nakajima K, Mikoshiba K, Miyata T, Kudo C, Ogawa M (1997) Disruption of hippocampal development in vivo by CR-50 mAb against reelin. Proc Natl Acad Sci USA 94:8196–8201CrossRefPubMedGoogle Scholar
  39. Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K (1995) The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14:899–912CrossRefPubMedGoogle Scholar
  40. Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y (1991) Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 30:750–757CrossRefPubMedGoogle Scholar
  41. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738PubMedGoogle Scholar
  42. Rakic P, Caviness VS Jr (1995) Cortical development: view from neurological mutants two decades later. Neuron 14:1101–1104CrossRefPubMedGoogle Scholar
  43. Rao MS, Shetty AK (2004) Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur J Neurosci 19:234–246CrossRefPubMedGoogle Scholar
  44. Riban V, Bouilleret V, Pham-Le BT, Fritschy JM, Marescaux C, Depaulis A (2002) Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience 112:101–111CrossRefPubMedGoogle Scholar
  45. Rice DS, Curran T (2001) Role of the reelin signaling pathway in central nervous system development. Annu Rev Neurosci 24:1005–1039CrossRefPubMedGoogle Scholar
  46. Scharfman HE, Goodman JH, Sollas AL (2000) Granule-like neurons at the hilar/CA3 pyramidal cell border after status epilepticus and their synchrony with area CA3 pyramdial cells: functional implications of seizure-induced neurogenesis. J Neurosci 20:6144–6158PubMedGoogle Scholar
  47. Sheldon M, Rice DS, D’Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, Howell BW, Cooper JA, Goldowitz D, Curran T (1997) Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice 389:730–733Google Scholar
  48. Soriano E, Del Rio JA (2005) The cells of Cajal-Retzius: still a mystery one century after. Neuron 46:389–394CrossRefPubMedGoogle Scholar
  49. Stanfield BB, Cowan WM (1979) The morphology of the hippocampus and dentate gyrus in normal and reeler mice. J Comp Neurol 185:393–422CrossRefPubMedGoogle Scholar
  50. Stegen M, Young CC, Haas CA, Zentner J, Wolfart J (2009) Increased leak conductance in dentate gyrus granule cells of temporal lobe epilepsy patients with Ammon’s horn sclerosis. Epilepsia 50:646–653CrossRefPubMedGoogle Scholar
  51. Suzuki F, Junier MP, Guilhem D, Sorensen JC, Onteniente B (1995) Morphogenetic effect of kainate on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor. Neuroscience 64:665–674CrossRefPubMedGoogle Scholar
  52. 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 64:194–201PubMedGoogle Scholar
  53. Tissir F, Goffinet AM (2003) Reelin and brain development. Nat Rev Neurosci 4:496–505CrossRefPubMedGoogle Scholar
  54. Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J (1999) Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97:689–701CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Experimental Epilepsy Research, NeurocenterUniversity of FreiburgFreiburgGermany
  2. 2.Institute of Anatomy and Cell BiologyUniversity of FreiburgFreiburgGermany

Personalised recommendations