Pathogenesis of experimentally-induced heterotopia, with special reference to apoptosis and gap junctional communication.

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Cortical malformations such as cortical dysplasia and heterotopia constitute the underlying pathology of epilepsy and mental retardation. It is thus important to elucidate the pathogenesis of these migration disorders from the cellular and molecular viewpoints based upon animal experiments.We performed experiments in which embryonic mice were exposed to low-dose X- irradiation at the mid-gestational period. Low-dose irradiation as low as 0.25 Gy induced decelerated migration of cortical neurons during the embryonic period. In addition, the effect of radiation remained at least up until 3-week postnatal in terms of disorganized neuronal allocation with respect to the birthdate. With time of further maturation in the neocortex, the cytoarchitecture as revealed by the pattern of distribution of the labeled neurons, returned closely to that found in non-irradiated control animals. Considering the fact that the number of labeled cells per unit cortical area decreased considerably from 3-week to 8-week postnatal, it is conceivable that apoptotic cell death might have occurred in aberrantly placed neurons.Secondly, we attempted to study connexin43-null mutant mice to elucidate the significance of intercellular gap junctional communication during cortical histogenesis, with special reference to neuronal migration. Our result indicated a significant delay in neocortical neuronal migration in the connexin43-null mutants, suggesting a possible role of connexin43 in this process through yet unidentified mechanisms.