Neural Grafts and Injury-Induced Hippocampal Dysfunction

描述(申请人提供)：由急性癫痫发作或头部损伤造成的海马区损害最初导致癫痫样改变，然后导致以慢性癫痫为例的海马区功能障碍，以及学习和记忆障碍。200多万美国人患有癫痫，许多癫痫患者患有对抗癫痫药物耐药的慢性癫痫发作，以及学习和记忆功能障碍。因此，需要能够阻止慢性癫痫发展和海马区损伤后学习和记忆功能障碍的治疗干预措施。该项目的中心焦点是开发理想的细胞移植策略，以防止海马区最初的沉淀损伤(IPI)进展为慢性癫痫，以及学习记忆功能和齿状神经发生的长期损害。我们将分析三种不同类型供体细胞的移植效果：胎儿有丝分裂后海马细胞、来自胎儿海马区的神经干细胞(NSCs)和来自前脑室下区的NSCs。第一种假设是，在损伤后不久将胚胎有丝分裂后的海马细胞或未成熟的神经干细胞移植到海马区，可以避免IPI进展为以自发性反复运动性癫痫(SRMS)为特征的慢性癫痫。第二种假说是，在损伤后不久将胚胎海马区细胞或神经干细胞移植到海马区，可以有效地防止损伤所致的学习记忆功能障碍和齿状神经发生。这些假说将通过广泛的免疫组织化学、视频脑电(Video-EEC)以及学习和记忆分析在年轻成年F344大鼠身上进行验证，这些大鼠经历了腹膜内红藻氨酸诱导的急性癫痫发作和海马区损伤，这是一种颞叶癫痫模型。第一个具体目标是严格分析致痫后4d将胚胎海马细胞和神经干细胞移植到海马区，以替代丢失的神经元，阻断致痫改变和SRMS的发生的效果。第二个具体目标是量化胚胎海马细胞和神经干细胞在癫痫致伤后4天移植到海马区的有效性，以防止或最大限度地减少海马区依赖学习记忆功能和齿状神经发生的长期缺陷。可以预见，如上所述的双侧胚胎海马细胞或神经干细胞移植可以抑制损伤后早期发生的多种致痫改变，重建受损的海马回路，从而防止或减少海马区损伤导致的慢性癫痫的发展和学习记忆功能的障碍。总而言之，拟议的实验对于开发APT治疗策略具有巨大的价值，该策略可以预防慢性癫痫和成人海马区损伤后的学习和记忆障碍。

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.