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.

尽管癫痫是常见的神经系统问题，但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为癫痫发作，并了解大脑如何终止同步，从而使癫痫发作结束。在这一赠款期间，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+ATPase作为摄取机制在神经元活动期间和之后的[K+] 0从升高水平中恢复中的摄取机制的作用将通过测量[K+] 0的自上限水平和恢复速率来测试在正常的成年大鼠和在癫痫发作期间和之后用星形胶质细胞抑制剂治疗的大鼠中体内体内，由电刺激诱导的癫痫发作，化学抽搐剂以及在扩散抑郁症的过程中和之后。在非突触场爆发期间，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处理后，将在齿状回的体外进一步检验该假设。确定未成熟大脑中[K+] 0的异常调节是否是由于神经元Na+/K+ATPase的发育不成熟，在成人体内和体外和体外的自上限水平和恢复速率将比较少年大鼠（PN 10-25）。最后，将开发对[K+] 0的活性依赖性变化的定量解释，这些变化已迄今已衡量并将在此赠款期间收集。要检验的第二个假设是，颗粒细胞的细胞内pH的改变对于末期齿状回的癫痫发作放电至关重要。首先，在体内和体外的pH值和体外的细胞内pH波动及其与癫痫发作的对应以及对正常神经胶质功能的对应关系，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。最后，为了确定细胞内pH的改变是否是癫痫发射排放的终止，改变癫痫发作持续时间的操作以及组织在测量细胞内pH的同时，将在体外进行泵送氢离子的能力。