Neural Grafts and Injury-Induced Hippocampal Dysfunction

描述（由申请人提供）：急性癫痫发作或头部损伤引起的海马损伤最初导致致癫痫变化，然后导致海马功能障碍，例如慢性癫痫以及学习和记忆障碍。超过200万美国人患有癫痫，许多癫痫患者患有慢性癫痫发作，对抗癫痫药物具有耐药性，并且学习和记忆功能障碍。因此，需要能够在海马损伤后阻断慢性癫痫发展和学习记忆功能障碍的治疗干预。该项目的中心重点是开发理想的细胞移植策略，以防止海马中的初始诱发性损伤（IPI）进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功效：胎儿有丝分裂后海马细胞、来自胎儿海马的神经干/祖细胞（NSC）和来自前室下区的NSC。第一个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NSC移植到海马中，避免了IPI进展为以自发性复发性运动性癫痫发作（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NSC移植到海马中对于预防损伤诱导的学习和记忆功能以及齿状神经发生的缺陷是有效的。这些假设将进行广泛的免疫组化，视频脑电图（video-EEC），学习和记忆分析，在年轻的成年F344大鼠进行腹膜内红藻氨酸诱导的急性癫痫发作和海马损伤，颞叶癫痫模型。第一个具体目标将严格分析在癫痫诱导的损伤后4天将胎儿海马细胞和NSC移植到海马中以替代丢失的神经元并阻断致癫痫变化和SRMS发生的有效性。第二个具体目标将量化在癫痫发作诱导的损伤后4天将胎儿海马细胞和NSC移植到海马中以预防或最小化海马依赖性学习和记忆功能以及齿状神经发生的长期缺陷的有效性。可以设想，如上所述的胎儿海马细胞或NSC的双侧移植抑制了在损伤后早期阶段期间发生的多种致癫痫变化，重建了被破坏的海马回路，从而防止或最小化海马损伤诱导的慢性癫痫发展和学习和记忆功能的缺陷。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apt治疗策略具有巨大价值。

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.