Neural Grafts and Injury-Induced Hippocampal Dysfunction

描述（由申请人提供）：由急性癫痫发作或头部损伤引起的海马病变最初导致癫痫性改变，然后导致以慢性癫痫为例的海马功能障碍，以及学习和记忆障碍。超过200万美国人患有癫痫，许多癫痫患者患有抗癫痫药物抗药性的慢性癫痫发作，以及学习和记忆功能障碍。因此，在海马损伤后，需要能够阻断慢性癫痫发展和学习记忆功能障碍的治疗干预措施。本项目的中心重点是发展理想的细胞移植策略，以防止海马初始沉淀损伤（IPI）发展为慢性癫痫和学习记忆功能和齿状神经发生的长期损伤。我们将分析三种不同供体细胞类型的移植物的疗效：胎儿有丝分裂后海马细胞、来自胎儿海马的神经干/祖细胞（NSCs）和来自前心室下区的NSCs。第一种假设是，在损伤后不久将胎儿有丝分裂后海马细胞或未成熟的NSCs移植到海马中，可以避免IPI发展为以自发性复发性运动发作（SRMS）为特征的慢性癫痫。第二种假设是，在损伤后不久将胎儿海马细胞或NSCs移植到海马中可有效预防损伤引起的学习记忆功能缺陷和齿状神经发生。这些假设将通过广泛的免疫组织化学、视频脑电图（video-EEC）和学习和记忆分析在年轻成年F344大鼠中进行腹腔注射kainic酸诱导的急性癫痫发作和海马损伤（颞叶癫痫模型）来验证。1st Specific Aim将严格分析在癫痫性损伤后4天将胎儿海马细胞和NSCs移植到海马中，以替代丢失的神经元，并阻断癫痫性改变和SRMS的发生。第二个特定目标将量化在癫痫诱发损伤后4天将胎儿海马细胞和NSCs移植到海马中的有效性，以预防或减少海马依赖的学习记忆功能和齿状神经发生的长期缺陷。我们设想，上述双侧胚胎海马细胞或NSCs移植可抑制损伤后早期发生的多种致痫性变化，重建被破坏的海马回路，从而预防或减少海马损伤引起的慢性癫痫发展和学习记忆功能缺陷。总的来说，所提出的实验对于开发预防成人海马损伤后慢性癫痫和学习记忆障碍的适当治疗策略具有巨大的价值。

DESCRIPTION (provided by applicant): Hippocampal lesions inflicted by acute seizures or head injury initially lead to epileptogenic changes, and then to hippocampal dysfunction exemplified by chronic epilepsy, and learning and memory impairments. More than two-million Americans suffer from epilepsy, and many people with epilepsy have chronic seizures that are resistant to antiepileptic drugs, and learning and memory dysfunction. Thus, therapeutic interventions capable of blocking both chronic epilepsy development and learning and memory dysfunction, after the hippocampal injury, are needed. The central focus of this project is on the development of ideal cell transplantation strategies that prevent the progression of initial precipitating injury (IPI) in the hippocampus into chronic epilepsy and long-term impairments in learning and memory function and dentate neurogenesis. We will analyze the efficacy of grafts of three different donor cell types: fetal post-mitotic hippocampal cells, neural stem/progenitor cells (NSCs) from the fetal hippocampus, and NSCs from the anterior subventricular zone. The 1st hypothesis is that transplantation of fetal post-mitotic hippocampal cells or immature NSCs into the hippocampus shortly after the injury averts the progression of the IPI into chronic epilepsy characterized by spontaneous recurrent motor seizures (SRMS). The 2nd hypothesis is that grafting of fetal hippocampal cells or NSCs into the hippocampus shortly after the injury is efficacious for preventing the injury-induced deficits in learning and memory function and dentate neurogenesis. These hypotheses will be tested with wide-ranging immunohistochemical, video-electroencephalographic (video-EEC), and learning and memory analyses in young adult F344 rats undergoing intraperitoneal kainic acid induced acute seizures and hippocampal injury, a model of temporal lobe epilepsy. The 1st Specific Aim will rigorously analyze the efficacy of grafting of fetal hippocampal cells and NSCs into the hippocampus at 4 days after the seizure-induced injury for replacing the lost neurons, and blocking both epileptogenic changes and the occurrence of SRMS. The 2nd Specific Aim will quantify the effectiveness of transplantation of fetal hippocampal cells and NSCs into the hippocampus at 4 days after the seizure induced injury for preventing or minimizing long-term deficits in hippocampal-dependent learning and memory function and dentate neurogenesis. It is envisioned that bilateral grafting of fetal hippocampal cells or NSCs as above suppresses multiple epileptogenic changes that occur during the early post-injury phase, reconstruct the disrupted hippocampal circuitry and thereby prevent or minimize the hippocampal injury- induced chronic epilepsy development and deficits in learning and memory function. Collectively, the proposed experiments have immense value for the development of apt treatment strategy that prevents both chronic epilepsy and learning and memory impairments after hippocampal injury in adults.