MECHANISMS OF GABA-B INHIBITION AND EPILEPSY

GABA-B 抑制和癫痫的机制

基本信息

批准号：
2273017
负责人：
Kevin D Phelan
金额：
$ 12.91万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-01 至 1999-02-28
项目状态：
已结题

项目摘要

Presynaptic gamma-aminobutyric acid (GABA) receptors play a central role in regulating excitatory and inhibitory synaptic transmission in the mammalian central nervous system. it has been proposed that the ability of these receptors to regulate glutamate release may be altered during development and in epilepsy. Recently a novel "desensitizing" GABAb receptor was discovered which participates in the regulation of excitatory transmission at functionally distinct glutamatergic synapses. This raises the possibility that changes in the type of receptor expressed during development or m epileptic brain may contribute to alterations in GABAb receptor function. The long term objective of the proposed research is to investigate the mechanism(s) underlying presynaptic GABAb receptor-mediated regulation of excitatory (glutamatergic) synaptic transmission during normal cerebral cortical development and in epileptic neocortex. The specific aims of the proposed research are: 1) to determine differences in the pharmacological and developmental profiles of the novel "desensitizing" and classical non- desensitizing presynaptic GABAb receptors which inhibit the cortical release of glutamate; 2) to compare the underlying receptor-effector coupling mechanism(s) used by these receptors, and determine if second messenger modulation of receptor function changes during development; and 3) to assess whether presynaptic GABAb receptor function is altered in human epileptic cortex, and if so, to determine the mechanism(s) underlying these changes. These aims will be achieved using standard whole-cell voltage-clamp (patch-clamp) and intracellular current-clamp recording techniques. Spontaneous and evoked glutamatergic synaptic events will be used to monitor the effects of exogenous activation of presynaptic GABAb receptors. These studies will be performed in embryonic rat cortical cell cultures, neonatal and adult rat brain slices, and human neocortical brain slices prepared from surgical waste tissue removed from patients with epilepsy during temporal lobe resection for relief from intractable seizures. The proposed research will provide important information immediately relevant to our understanding of the role of presynaptic GABAb receptors in the regulation of the release of glutamate during normal development and under pathophysiological (epileptic) conditions. More importantly, this work may have implications for the eventual design and use of novel therapeutic strategies based on targeting of drugs at specific subsets of functionally distinct glutamate releasing terminals. This approach may prove useful in the treatment of epilepsy and other pathophysiological conditions which involve overactivation of glutamate receptors.

突触前γ-氨基丁酸（GABA）受体起着核心作用在调节兴奋性和抑制性突触传播中哺乳动物中枢神经系统。有人提出能力在调节谷氨酸释放的这些受体中，可能会改变发育和癫痫。最近一部小说“脱敏” Gabab 发现受体参与调节功能不同的谷氨酸能突触的兴奋性传播。这增加了受体类型的变化的可能性在发育或癫痫大脑发育期间表达可能有助于 GABAB受体功能的改变。长期目标的拟议的研究是研究基本机制突触前GABAB受体介导的兴奋性调节正常皮质期间（谷氨酸能）突触传播发育和癫痫新皮层。提议的具体目的研究是：1）确定药理学和小说的“脱敏”和经典非 - 的发展概况脱敏的突触前GABAB受体抑制皮质释放谷氨酸； 2）比较基础受体效应器这些受体使用的耦合机制，并确定是否第二发育过程中受体功能变化的信使调节；和 3）评估突触前GABAB受体功能是否改变人类癫痫皮质，如果是这样，以确定机制这些变化的基础。这些目标将使用标准实现全细胞电压钳（斑块钳）和细胞内电流钳记录技术。自发和诱发的谷氨酸能突触事件将用于监测外源激活的影响突触前GABAB受体。这些研究将在胚胎中进行大鼠皮质细胞培养物，新生儿和成年大鼠脑切片，以及由手术废物组织制备的人类新皮层脑切片在颞叶切除期间从患有癫痫患者的患者中移除缓解顽固性癫痫发作。拟议的研究将提供重要信息立即与我们的理解有关突触前GABAB受体在调节中的作用正常发育和病理生理期间谷氨酸（癫痫）条件。更重要的是，这项工作可能有影响最终设计和使用新颖的治疗策略在功能上不同的谷氨酸的特定子集中靶向药物释放终端。这种方法可能对治疗癫痫和其他涉及的病理生理状况谷氨酸受体过度活化。