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

皮质畸形，如皮质发育不良和异位，构成癫痫和智力低下的潜在病理。因此，在动物实验的基础上，从细胞和分子的角度阐明这些迁移障碍的发病机制是非常重要的。我们进行了胚胎小鼠在妊娠中期接受低剂量X射线照射的实验。低剂量辐射(低至0.25Gy射线)可诱导胚胎期皮质神经元减速迁移。此外，就出生日期而言，辐射的影响至少一直持续到出生后3周。随着新皮质进一步成熟，标记神经元的分布模式所揭示的细胞结构接近于未受照射的对照动物的细胞结构。考虑到从出生后3周到8周，单位皮质面积上标记细胞的数量显著减少，可以想象在异常放置的神经元中可能发生了细胞凋亡。第二，我们试图以连接蛋白43缺失的突变小鼠为研究对象，阐明细胞间缝隙连接通讯在皮质组织发生中的意义，特别是神经元迁移。我们的结果表明，在连接蛋白43缺失突变体中，新皮质神经元的迁移显著延迟，提示连接蛋白43可能通过尚未确定的机制在这一过程中发挥作用。

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.