A GENETIC ANIMAL-MODEL OF HUMAN NEOCORTICAL HETEROTOPIA ASSOCIATED WITH SEIZURES

Malformations of the human necoortex are commonly associated with deve lopmental delays, mental retardation, and epilepsy. This study describ es a novel neurologically mutant rat exhibiting a forebrain anomaly re sembling the human neuronal migration disorder of double cortex. This mutant displays a telencephalic internal structural heterotopia (tish) that is inherited in an autosomal recessive manner. The bilateral het erotopia is prominent below the frontal and parietal neocortices but i s rarely observed in temporal neocortex. Neurons in the heterotopia ex hibit neocortical-like morphologies and send typical projections to su bcortical sites; however, characteristic lamination and radial orienta tion are disturbed in the heterotopia. The period of neurogenesis duri ng which cells in the heterotopia are generated is the same as in the normotopic neocortex; however, the cells in the heterotopia exhibit a ''rim-to-core'' neurogenetic pattern rather than the characteristic '' inside-out'' pattern observed in normotopic neocortex. Similar to the human syndrome of double cortex, some of the animals with the tish phe notype exhibit spontaneous recurrent electrographic and behavioral sei zures. The tish rat is a unique neurological mutant that shares severa l features with a human cortical malformation associated with epilepsy . On the basis of its regional connectivity, histological composition, and period of neurogenesis, the heterotopic region in the tish rat is neocortical in nature. This neurological mutant represents a novel mo del system for investigating mechanisms of aberrant neocortical develo pment and is likely to provide insights into the cellular and molecula r events contributing to seizure development in dysplastic neocortex.