HIPPOCAMPAL NETWORK STRUCTURE AND FUNCTION IN EPILEPSY

癫痫中的海马网络结构和功能

• 批准号: 2263370
• 负责人: Robert S Sloviter
• 金额: $ 25.64万
• 依托单位: HELEN HAYES HOSPITAL
• 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/2263370
• 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，其特征是 由起源于内部或附近的自发神经元癫痫活动引起 海马体。 人类癫痫海马体表现出 细胞损失和突触重组的特征模式 幸存的神经元。该应用程序的基本假设是 这种细胞丢失的模式以及由此产生的神经重组 途径在某种程度上与该疾病的病理生理学有因果关系 临床障碍。电生理学和解剖学实验 旨在研究缺陷可能产生的功能后果 海马网络的结构和功能。两只动物 表现出不同的模型。人类癫痫状态的特征， 即细胞损失、轴突萌芽和自发性癫痫发作 仔细表征和比较。 体内电生理学 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 突触重组发生之前和之后的损伤。体外 来自同一动物的海马切片将用于研究 体内鉴定的病理生理学细胞机制 实验。病理生理缺陷的体内鉴定 其独特之处在于其体外保存和研究 这些研究。齿状颗粒细胞对的细胞内记录 颗粒细胞-篮细胞对将揭示兴奋-抑制 受损海马突触前后的相互作用 重组发生。光和电子显微镜-免疫细胞化学 方法将用于识别突触重组途径 他们改变的电路的术语。额外的研究将尝试 防止癫痫引起的细胞损伤后的轴突发芽 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 被认为介导发芽反应的因素。长期来看 拟议研究的目标是确定如何破坏 海马神经网络导致海马的发育 主细胞过度兴奋可能是一个显着的 癫痫状态的特征。细胞机制的鉴定 这些异常网络属性的基础将导致 了解癫痫的过程和合理发展 新药可用于治疗这种通常难以治愈的疾病 神经系统疾病。