Reelin deficiency causes granule cell dispersion in epilepsy
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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.
KeywordsHippocampus 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).
- 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
- 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
- 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
- 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
- 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