HIPPOCAMPAL NETWORK STRUCTURE/FUNCTION IN EPILEPSY

摘要颞叶癫痫是一种常见的神经系统疾病。 通过起源于内部或附近的自发神经元癫痫活动 海马体。人类癫痫患者的海马体表现出 细胞丢失和突触重组的特征模式 幸存的神经元。此应用程序的基本假设是 这种细胞丢失的模式和由此导致的神经细胞重组 通路在某种程度上与这种疾病的病理生理学有关。 临床障碍。电生理和解剖学实验已经 旨在研究缺陷可能产生的功能后果 在海马网的结构和功能上。两只动物 展示不同风格的模特。人类癫痫状态的特征， 即细胞丢失、轴突萌发和自发性癫痫发作 仔细地刻画和比较。活体电生理 实验将利用海马区诱发的场电位来研究 实验后整体动物的抑制性和兴奋性 在突触重组之前和之后的损伤。离体 来自相同动物的海马片将被用来研究 体内发现的病理生理学的细胞机制 实验。一例病理生理缺陷的活体鉴定 而它的体外保存和研究是一个独特的特点 这些研究。齿状颗粒细胞对的细胞内记录 颗粒细胞-篮子细胞对将显示兴奋抑制 突触前后受损海马区的相互作用 重组就会发生。光镜和电子显微镜-免疫细胞化学 方法将被用来识别突触重组的通路 关于它们改变的电路的术语。其他研究将尝试 防止癫痫发作诱导的细胞损伤后轴突萌发 为了阐明突触的功能后果 重组。这将通过注射促进生长的抗体来完成。 被认为是调节萌芽反应的因素。长期的 拟议研究的目标是确定网络中断是如何 海马神经元网络导致海马区发育 主细胞的超兴奋性很可能是一个显著的 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 对癫痫发病过程的认识与合理发展 治疗这种常常是医学上难以治愈的疾病的新药 神经性疾病。

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.