An approach for anti-sense therapy based on the establishment of an animal model for the epileptogenic cortical malformations

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Focal cortical malformations as a result of cell migration disorder are often associated with intractable epilepsy. By using the rats underwent neonatal cortical freeze-lesion (FL), as a model for human polymicrogyria, we studied [Cl^-]_i and the GABA/glycine effects during formation of the microgyrus. GABA/glycine-induced depolarizations and Ca^<2+> influxes were observed in the upper part of FL in which [Cl^-]_i were increased. Consistently, mRNA expression of NKCC1 (accumulates Cl^-) was up-regulated whereas that of KCC2 (extrudes Cl^-) was downregulated. Above characteristics are similar to the known characteristics of migrating cortical plate cells. Thus, cortical plate cells near by FL might regain or preserve the immature characteristics of Cl^-homeostasis and GABA/glycine actions, so that they could migrate into the FL to form microgyrus expressing hyperexcitability later on.We also investigated NKCC1 and KCC2 expressions in the human focal cortical dysplasia (FCD) tissue, characterized by disorganized lamination and cytomegalic dysplastic cells, from patients of intractable epilepsy. KCC2 mRNA and protein were decreased in small-sized dysplastic neurons as compared to non-dysplastic neurons in histologicaly normal portion. These results suggest that decreases in KCC2 expression in small-sized dysplastic neurons might change their Cl^-homeostasis, so that impairment of GABAergic actions could occur in FCD being involved in epileptogenesis.