HIPPOCAMPAL NETWORK STRUCTURE/FUNCTION IN EPILEPSY

癫痫中的海马网络结构/功能

• 批准号: 2676666
• 负责人: Robert S Sloviter
• 金额: $ 29.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2676666
• 关键词: cell death; central neural pathway /tract; disease /disorder model; electrophysiology; evoked potentials; experimental brain lesion; granule cell; hippocampus; immunoelectron microscopy; intercellular connection; laboratory rat; model design /development; mossy fiber; neural degeneration; neural inhibition; neural plasticity; neural transmission; neuroanatomy; neurogenesis; neuronal transport; neurophysiology; neurotoxins; neurotrophic factors; neutralizing antibody; partial seizure; stress proteins; synaptogenesis; temporal lobe /cortex disorder

Temporal lobe epilepsy is a common neurological disorder characterized by spontaneous neuronal seizure activity that originates within or near the hippocampus. The human epileptic hippocampus exhibits a characteristic pattern of cell loss and a synaptic reorganization of surviving neurons. It is the basic assumption of this application that this pattern of cell loss and the resulting reorganization of neural pathways are in some way causally related to the pathophysiology of this clinical disorder. Electrophysiological and anatomical experiments have been designed to study the possible functional consequences of defects in the structure and function of the hippocampal network. Two animal models that exhibit different . features of the human epileptic state, i.e. cell loss, axon sprouting, and spontaneous seizures, will be carefully characterized and compared. In vivo electrophysiological experiments will utilize hippocampal evoked field potentials to study inhibition and excitability in the whole animal after experimental lesions, both before and after synaptic reorganization occurs. In vitro hippocampal slices from the same animals will be used to study the cellular mechanisms of the pathophysiology identified in the in vivo experiments. The in vivo identification of a pathophysiological defect and its preservation and investigation in vitro is a unique feature of these studies. Intracellular recordings of dentate granule cells pairs and granule cell-basket cell pairs will reveal excitatory-inhibitory interactions in damaged hippocampi, both before and after synaptic reorganization occurs. Light and electron microscopic-immunocytochemical methods will be used to identify synaptically reorganized pathways in terms' of their altered circuitry. Additional studies will attempt to prevent the axon sprouting that follows seizure-induced cell injury in order to elucidate the functional consequences of synaptic reorganization. This will be done by infusion with antibodies to growth factors that are thought to mediate the sprouting response. The long-term goal of the proposed studies is to determine how a disruption in the hippocampal neuronal network leads to the development of hippocampal principal cell hyperexcitability that is likely to be a significant feature of the epileptic state. Identification of the cellular mechanisms that underlie these abnormal network properties will lead to an understanding of the epileptic process and the rational development of new drugs useful in the treatment of this often medically intractable neurological disorder.

颞叶癫痫是一种常见的神经系统疾病， 通过自发性神经元癫痫发作活动， 海马体 人类癫痫海马体表现出 细胞丢失的特征模式和突触重组， 存活的神经元本申请的基本假设是， 这种细胞丢失的模式以及由此导致的神经细胞的重组 这些通路在某种程度上与这种疾病的病理生理学有因果关系。 临床病症电生理学和解剖学实验 设计用于研究缺陷的可能功能后果 海马网络的结构和功能。两个动物 展示不同的模型。人类癫痫状态的特征， 即细胞损失，轴突发芽，自发性癫痫发作，将是 仔细地描述和比较。 体内电生理 实验将利用海马诱发场电位来研究 实验后整个动物的抑制性和兴奋性 损伤，在突触重组发生之前和之后。体外 来自相同动物的海马切片将用于研究 在体内确定的病理生理学的细胞机制 实验病理生理缺陷的体内鉴定 它的保存和体外研究是一个独特的特点， 这些研究。齿状突颗粒细胞对的细胞内记录 而颗粒细胞-篮状细胞对将揭示兴奋-抑制性 在受损的突触前和突触后， 重组发生。光镜和电镜-免疫细胞化学 方法将用于识别突触重组的途径， 他们改变了的电路更多的研究将试图 防止轴突发芽后，神经元损伤诱导的细胞损伤， 为了阐明突触的功能后果， 重组。这将通过注入生长抗体来完成 被认为是介导发芽反应的因素。长期 拟议研究的目标是确定如何破坏 海马神经元网络导致海马的发育 主细胞过度兴奋，这可能是一个重要的 癫痫的症状识别细胞机制 这些异常网络属性的基础将导致 了解癫痫的过程和合理的发展， 用于治疗这种通常难以治愈的疾病的新药 神经紊乱