Treating Cortical Epilepsy with Interneuron Transplants

描述(申请人提供)：尽管癫痫发作障碍的治疗取得了进步，但需要手术治疗的难治性癫痫仍然是一个严重的问题。通过将抑制性中间神经元移植到癫痫灶来治疗癫痫的概念已经有十多年的历史了，但还没有产生临床上有用的方法。然而，最近关于皮质中间神经元起源和规范的研究需要对这一问题进行新的研究。我们建议使用中间神经元前体细胞脑内移植来治疗局灶性诱导的成年小鼠皮层慢性癫痫发作。这项研究结合了威尔-康奈尔医学院两个实验室的专业知识。PI是神经外科的助理教授，他利用体内电生理学和内在光学成像技术研究癫痫啮齿动物模型中皮质癫痫发作的传播。这位合作者是精神病学助理教授，通过将小鼠皮质下胚胎前脑的中间神经元前体细胞移植到出生后的皮质中，研究小鼠皮质中间神经元亚型的规范。 在目标1中，研究人员将优化将神经元间祖细胞移植到破伤风毒素(TTX)诱导的慢性癫痫灶中的方案。此外，还将研究慢性癫痫发作对神经元间迁移、存活和分化的影响。初步数据表明，就像将神经前体细胞移植到正常成年小鼠的皮质中一样，移植到TTX诱导的癫痫灶也能导致大量细胞的迁移、存活和神经元间分化。 目的2将通过在TTX模型中确定移植的中间神经元抑制癫痫样活动的能力来测试系统水平的功能。在移植前几周和移植后几个月，将通过同步遥测和视频监测来评估癫痫样活动。通过移植神经元间祖细胞池来减少癫痫样放电的能力将与载体和基于细胞的对照进行比较。这一结果将加强未来使用神经元间祖细胞定向干细胞的研究的理论基础，并探索使用神经元间祖细胞作为抗癫痫药物的细胞递送系统。 这一提议所产生的进展应有助于预防或阻断局灶性病变引起的顽固性癫痫的发生。这项研究在越来越多地面向临床的研究中的应用将通过咨询西奥多·施瓦茨博士来实现。西奥多·施瓦茨博士是一名执业神经外科医生，也是WMC癫痫外科中心的研究主任。

DESCRIPTION (provided by applicant): Despite advances in the treatment of seizure disorders, medically intractable epilepsy requiring surgical treatment remains a serious problem. The concept of treating seizures by grafting inhibitory interneurons into seizure foci is more than a decade old, but has yet to lead to clinically useful approaches. However, recent studies on the origins and specification of cortical interneurons warrant a new examination of this issue. We propose to use intracerebral grafts of interneuron precursors to treat chronic seizures that are focally induced in the adult mouse cortex. This study combines the expertise of two laboratories at Weill-Cornell Medical College. The PI, an Assistant Professor of Neurological Surgery, studies the propagation of cortical seizures in rodent models of epilepsy using in vivo electrophysiology and intrinsic optical imaging. The co-investigator, an Assistant Professor of Psychiatry, studies the specification of cortical interneuron subtypes in mice using transplantation of interneuron progenitors from the subcortical embryonic forebrain into the postnatal cortex. In Aim 1 the investigators will optimize the protocol for transplantation of interneuron progenitors into Tetanus Toxin (TTx)-induced chronic epileptic foci. In addition, effects of chronic seizures on interneuron migration, survival, and differentiation will be examined. Preliminary data suggest that, like transplants interneuron progenitors into the cortex of normal adult mice, transplants into TTx-induced seizure foci also result in migration, survival, and interneuronal differentiation of substantial numbers cells. Aim 2 will test the system-level functionality of transplanted interneurons by determining their ability to suppress epileptiform activity in the TTx model. Epileptiform activity will be assessed by simultaneous telemetry and video monitoring for several weeks before and several months following transplantation. The capacity to reduce epileptiform discharges with transplants of interneuron progenitor pools that are enriched for distinct interneuron subgroups will be compared to vehicle and cell-based controls. The results will strengthen the rationale for future studies using interneuron-progenitor directed stem cells, and also to explore the use of interneuron progenitors as a cell-based delivery system of anti-epileptic agents. The advances resulting from this proposal should inform efforts to prevent or interrupt intractable epileptogenesis resulting from focal lesions. The application of this research to increasingly clinically-oriented studies will be achieved by consultation with Dr. Theodore Schwartz, a practicing neurosurgeon who is the Director of Research at the Center for Epilepsy Surgery at WMC.