DEVELOPMENT AND EPILEPTOGENESIS OF A CNS SYNAPSE

中枢神经系统突触的发育和癫痫发生

• 批准号: 3396123
• 负责人: PHILIP A SCHWARTZKROIN
• 金额: $ 12.72万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-08-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3396123
• 关键词: cerebral ischemia /hypoxia; electrical potential; electroencephalography; electron microscopy; electrophysiology; gamma aminobutyrate; hippocampus; histochemistry /cytochemistry; immature animal; immunocytochemistry; laboratory rabbit; mature animal; membrane transport proteins; neural plasticity; neuroanatomy; neurogenesis; neuropharmacology; neurotransmitters; newborn animals; partial seizure; silver impregnation; spreading cortical depression; synapses

In normal immature cortical regions, synaptically-mediated inhibition is weak (compared to the normal adult), and develops relatively slowly. As the major inhibitory neurotransmitter in mammalian cortical structures, Gamma-aminobutyric (GABA) must plan an important role in determining the level of excitability of this tissue. Many studies of epilepsy have demonstrated that blockade of GABA-mediated inhibition can lead to epileptiform activity. Further, there appears to be a decrease of GABA terminals in chronic epileptic foci. Since the brain does appear to be particularly seizure prone at some early stages of development, it would be of interest to know whether and how such seizure susceptibility relates to the development of GABA-mediated inhibition. We will explore this question by correlating data from intracellular recordings in rabbit hippocampal neurons (in vitro slices) with thresholds for seizure generation in intact, maturing animals. In the process, we propose to study mechanisms for seizure onset, using the hippocampal slice as a simplified model system. Spontaneous and evoked seizure-like spreading depression and after discharge are generated in slices from immature rabbit hippocampus. Particular attention will be given to the role of inhibitory postsynaptic potentials (IPSPs) as the protective process which maintains cells at a hyperpolarized level and limits spread of excitability. In addition, the influence of extracellular potassium on PSPs and cellular excitability will be evaluated, and the contribution of the Na+, K+ ATPase pump studied. In parallel studies, we will focus on the development of the GABA/GAD (glutamic acid decarboxylase - the GABA synthesizing enzyme) system. Using electrophysiologic and pharmacologic techniques, we will study the development of IPSP potency and GABA efficacy in hippocampal neurons. Localization of GABA/GAD in local circuit neurons will be studied using GAD immunocytochemistry. These studies will yield information about the normal development of major control systems in hippocampus, and relate the efficacy of these systems to seizure susceptibility during development. Such data should also provide us with clues about how seizures develop - and might be controlled - in the maturing nervous system.

在正常的未成熟皮质区域，突触介导的抑制是 弱（与正常成人相比），并且发育相对缓慢。 作为 哺乳动物皮质结构中主要的抑制性神经递质， γ-氨基丁酸 (GABA) 必须在确定 该组织的兴奋性水平。 许多关于癫痫的研究表明 证明阻断 GABA 介导的抑制作用可以导致 癫痫样活动。 此外，GABA 似乎有所减少 慢性癫痫病灶的终末期。 因为大脑确实看起来是 在发育的某些早期阶段特别容易癫痫发作， 有兴趣了解这种癫痫易感性是否以及如何与 GABA 介导的抑制的发展。 我们将通过关联细胞内的数据来探讨这个问题 兔海马神经元（体外切片）的阈值记录 用于完整、成熟动物的癫痫发作。 在这个过程中，我们 提议使用海马切片研究癫痫发作的机制 作为一个简化的模型系统。 自发性和诱发性癫痫样发作 扩散的凹陷和放电后产生的切片 未成熟的兔子海马体。 将特别关注 抑制性突触后电位（IPSP）的保护作用 将细胞维持在超极化水平并限制扩散的过程 的兴奋性。 此外，细胞外钾的影响 将评估 PSP 和细胞兴奋性，并评估 研究了 Na+、K+ ATP 酶泵。 在并行研究中，我们将重点关注 GABA/GAD 的发展 （谷氨酸脱羧酶-GABA合成酶）系统。 使用 电生理学和药理学技术，我们将研究 海马神经元中 IPSP 效力和 GABA 效力的发展。 将使用 GAD 研究 GABA/GAD 在局部回路神经元中的定位 免疫细胞化学。 这些研究将提供有关专业正常发展的信息 海马体的控制系统，并将这些系统的功效与 发育过程中的癫痫易感性。 此类数据还应提供 为我们提供有关癫痫发作如何发生以及如何控制的线索 神经系统的成熟。