Reversibility of Neocortical Malformation

描述(由申请人提供)：大脑皮层畸形和癫痫发作之间的因果联系已得到很好的证实。手术切除可手术的畸形可以显著减少人类患者的癫痫发作，但对于不能手术或弥漫性皮质畸形，通常对药物治疗无效，必须开发替代疗法。新的治疗方法可能是从发现针对发育不良或移位的神经元的药理学药物，或从防止或消除已形成或正在形成的畸形的方法演变而来。我们假设，在发育过程中，有一个持续的结构可塑性时期，在此期间，神经元的迁移可以在移位的神经元中重新开始。我们进一步假设，在此期间，早期新皮质畸形可以通过适当激活或表达促进迁移的蛋白质，或通过消除干扰其他细胞迁移的细胞来退化。我们建议通过将我们的研究集中在皮质下带状异位(SBH)或双皮质综合征的新模型来检验这一假设。在初步研究中，我们发现，通过在迁移受损的神经元中重新表达双重皮质素(DCX)，可以防止该模型中的畸形形成。最重要的是，我们观察到畸形退化可能发生在发育早期畸形开始形成之后。在这个动物模型中了解异位退化的发育极限和机制是确定人类致痫神经元畸形是否可以通过重新激活正常神经元迁移来逆转的重要一步。公共卫生相关性：由大脑皮层发育畸形引起的癫痫障碍是最具挑战性的癫痫治疗形式之一。这种畸形通常是由于早期大脑成熟过程中神经元迁移的早期缺陷造成的。如果在早期发育期间停滞不前的神经元迁移可以重新启动，那么即使在畸形开始形成之后，这也开启了退化或逆转畸形的可能性。这里提出的实验将使用一种新的临床前模型来确定恢复正常迁移和逆转潜在致痫畸形形成的发育极限。

DESCRIPTION (provided by applicant): A causal link between malformations of cerebral cortex and seizures is well established. Surgical removal of operable malformations can significantly reduce seizures in human patients, however for inoperable or diffuse cortical malformations, often refractory to pharmacological therapy, alternative therapies must be developed. New treatments may evolve from either the discovery of pharmacological agents that target dysplastic or displaced neurons, or from approaches to prevent or eliminate formed or forming malformations. We hypothesize that during development there is a sustained period of structural plasticity during which time neuronal migration can be restarted in displaced neurons. We further hypothesize that during this period early neocortical malformations can be regressed by the appropriate activation or expression of proteins that promote migration, or by elimination of cells that interfere with the migration of other cells. We propose to test this hypothesis by focusing our studies on a novel model of sub cortical band heterotopia (sbh) or double cortex syndrome. In preliminary studies we have found that malformations in this model can be prevented from forming by re-expressing doublecortin (DCX) in migrationally impaired neurons. Most importantly, we observe that malformation regression can occur after a malformation begins to form in early development. Understanding the developmental limits and mechanisms of heterotopia regression in this animal model is an important step to determining whether epileptogenic neuronal malformations in humans may be reversed by reactivating normal neuronal migration. PUBLIC HEALTH RELEVANCE: Seizure disorders caused by developmental malformation of the cerebral cortex are one of the most challenging forms of epilepsy to manage. Such malformations are often formed by early deficits in migration of neurons during early brain maturation. If neurons stalled in there migration during early development can be re-started, then this opens up the possibility of regressing or reversing malformations even after they have begun to form. Experiments proposed here will use a novel pre-clinical model to establish the developmental limits of restoring normal migration and of reversing formation of potentially epileptogenic malformations.