IONIC HOMEOSTASIS AND SEIZURE REGULATION

离子稳态和癫痫调节

基本信息

批准号：
6531118
负责人：
Janet Lynn Stringer
金额：
$ 18.69万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2004-02-28
项目状态：
已结题

项目摘要

Although epilepsy is a common neurological problem, the mechanisms involved in the initiation and termination of seizure discharges are poorly understood. The long-term goal of this research is to understand how neurons become synchronized into seizure discharges and to understand how the brain terminates the synchronization allowing the seizure to end. In this grant period the focus will be on the role of the ionic environment in neuronal synchronization. First, the role of the neuronal Na+/K+ ATPase as an uptake mechanism in the recovery of the [K+]0 from elevated levels during and after neuronal activity will be tested by measuring the ceiling level and rate of recovery of the [K+]0 in vivo in normal adult rats and in rats treated with astrocyte inhibitors during and after seizures induced by electrical stimulation, administration of chemical convulsants and during and after spreading depression. This hypothesis will be further tested in vitro in the dentate gyrus during non-synaptic field bursts and during spreading depression in control conditions and after treatments designed to alter glial and neuronal uptake mechanisms. To determine whether the abnormal regulation of the [K+]0 in the immature brain is due to developmental immaturity of the neuronal Na+/K+ ATPase, the ceiling level and rate of recovery of the [K+]0 in vivo and in vitro in adult and juvenile rats (PN 10-25) will be compared. Finally, a quantitative interpretation of activity-dependent changes in [K+]0 that have been measured to date and that are to be gathered during this grant period will be developed. A second hypothesis to be tested is that alterations of the intracellular pH of the granule cells are critical for the termination of seizure discharges in the dentate gyrus. First, the intracellular pH fluctuations in vitro and extracellular fluctuations in pH in vivo and in vitro and their correspondence with the seizure discharges and dependence on normal glial function will be determined in normal rats and in rats treated with astrocyte inhibitors. Finally, to determine whether alterations in intracellular pH underlies the termination of the seizure discharges, manipulations that alter the seizure duration and the ability of the tissue to pump hydrogen ions will be carried out in vitro while measuring intracellular pH.

尽管癫痫是一种常见的神经系统问题，但人们对癫痫发作的启动和终止的机制知之甚少。这项研究的长期目标是了解神经元如何同步到癫痫发作放电，并了解大脑如何终止同步以允许癫痫发作结束。在此资助期内，重点将放在离子环境在神经元同步中的作用。首先，神经元 Na+/K+ ATP 酶作为摄取机制在神经元活动期间和之后 [K+]0 从升高水平恢复中的作用将通过测量 [K+]0 的上限水平和恢复率来测试在正常成年大鼠和用星形胶质细胞抑制剂治疗的大鼠中，在由电刺激、施用化学惊厥剂引起的癫痫发作期间和之后以及在抑郁症蔓延期间和之后进行体内试验。这一假设将在对照条件下以及旨在改变神经胶质和神经元摄取机制的治疗后的非突触场爆发期间和扩散抑制期间的齿状回中进一步进行体外测试。为了确定未成熟脑中[K+]0的异常调节是否是由于神经元Na+/K+ ATP酶发育不成熟所致，成人和体外[K+]0的体内和体外最高水平和恢复率。将比较幼年大鼠（PN 10-25）。最后，将对 [K+]0 的活动依赖性变化进行定量解释，这些变化迄今为止已测量并且将在本资助期间收集。要测试的第二个假设是，颗粒细胞的细胞内 pH 值的改变对于齿状回癫痫放电的终止至关重要。首先，将在正常大鼠和用星形胶质细胞抑制剂治疗的大鼠中确定体外细胞内pH波动和体内和体外细胞外pH波动及其与癫痫放电的对应性和对正常神经胶质功能的依赖性。最后，为了确定细胞内 pH 值的变化是否是癫痫放电终止的基础，将在体外进行改变癫痫持续时间和组织泵送氢离子能力的操作，同时测量细胞内 pH 值。