MODULATION OF INHIBITION IN THE NEONATAL HIPPOCAMPUS

新生儿海马抑制的调节

• 批准号: 2259512
• 负责人: Kevin J. Staley
• 金额: $ 9.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-26 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259512
• 关键词: GABA aminotransferase; GABA receptor; adenosine triphosphate; barbiturates; benzodiazepines; calcium flux; computer program /software; electrophysiology; evoked potentials; gamma aminobutyrate; generalized seizures; hippocampus; laboratory rat; mature animal; membrane potentials; muscimol; neural inhibition; newborn human (0-6 weeks); potassium; statistics /biometry; steroids; synapses; voltage /patch clamp

The training and research program described in this proposal supports the application for a Clinical Investigator Development Award for Dr. Kevin Staley. The proposed program will enable Dr. Staley to develop, under the supervision of Dr. David Prince, the skills necessary to pursue a research career in the area of pediatric epilepsy. The proposed research is motivated by the clinical difficulties involved in the treatment of neonatal seizures. The goal of this project is to evaluate two of the many possible hypotheses regarding the poor response of neonatal seizures to current anticonvulsant therapy. These hypotheses are based on the well-documented immaturity of the hippocampal GABAergic inhibitory system in the neonatal rat hippocampus, and the conditions under which GABAA receptor-mediated functions have been shown to be decreased. 1) Is modulation of GABAA inhibition by barbiturates and benzodiazepines different in the neonatal vs adult hippocampus? 2) Are the effects of the barbiturates and benzodiazepines on the GABAA system minimized under conditions which are likely to occur during neonatal seizures: depletion of presynaptic GABA, alteration in transmembrane ionic gradients, accumulation of intracellular free calcium, and the depletion of intracellular high-energy phosphates? The research will focus on the modulation of GABAA receptor-mediated inhibition in areas CA1 and CA3 of the in vitro hippocampal slice preparation, and will utilize the whole-cell patch clamp recording technique. Experiments include 1) Measurement of the effects of barbiturates and benzodiazepines on GABAA receptor-mediated evoked and spontaneous synaptic events; 2) Determination of the effects of barbiturates and benzodiazepines on GABAA synaptic events under conditions which are likely to occur during neonatal seizures 3) Assessment of alternative modulators of GABAergic inhibition such as GABA- aminotransferase inhibitors and steroids.

该提案中描述的培训和研究计划支持 凯文博士临床研究者开发奖申请 Staley。 拟议的计划将使Staley博士能够在 大卫·普林​​斯博士的监督，从事研究所需的技能 在儿科癫痫地区的职业。 拟议的研究是由涉及的临床困难引起的 新生儿癫痫发作的治疗。 这个项目的目标是 评估有关众多可能的假设中的两个关于不良反应的假设 新生儿癫痫发作对当前的抗惊厥疗法。 这些假设是 基于海马Gabaergic的有据可查的不成熟 新生大鼠海马中的抑制系统，以及 哪些GABAA受体介导的功能已显示出降低。 1）是对巴比妥类药物和苯二氮卓类药物对GABAA抑制的调节 新生儿与成人海马不同？ 2）是 在GABAA系统上的巴比妥类药物和苯二氮卓类药物最小化 新生儿癫痫发作期间可能发生的情况：耗尽 突触前GABA，跨膜离子梯度的改变， 细胞内无钙的积累，并耗尽 细胞内高能磷酸盐？ 该研究将重点介绍GABAA受体介导的调节 体外海马切片的CA1和CA3区域的抑制作用 准备，并将利用全细胞贴片夹记录 技术。 实验包括1）测量 GABAA受体介导的诱发的巴比妥类药物和苯二氮卓类药 自发突触事件； 2）确定效果 在条件下的GABAA突触事件上的巴比妥类药物和苯二氮卓类药物 在新生儿癫痫发作期间可能发生的3）评估 GABA能抑制的替代调节剂，例如GABA- 氨基转移酶抑制剂和类固醇。