激活环磷酸腺苷反应原件结合蛋白（CREB）降低耐药性颞叶癫痫大鼠脑组织GABAA受体表达的分子机制

耐药性癫痫患者病灶区的脑组织伽马氨基丁酸A受体（GABAA）显著减少，但机制不清；癫痫大鼠及难治性癫痫患者脑组织cAMP反应原件结合蛋白(CREB)明显增加，CREB可在基因转录水平调节GABAA受体的表达，因此推测耐药性癫痫患者脑组织中由于持续性的CREB激活导致GABAA受体表达减少从使得抗癫痫药物失效。本研究的目的是探讨耐药性癫痫大鼠脑组织GABAA受体减少的分子机制。首先制作耐药性颞叶癫痫大鼠模型，然后通过基因调控、信号通路阻断及激活等方法调控CREB的功能，观察耐药性癫痫大鼠GABAA表达、癫痫发作及脑电变化，记录海马细胞IPSC、mIPS以及细胞膜兴奋性，并用染色质免疫沉淀技术观察CREB与GABAA受体基因结合情况，从而证实CREB是否在降低耐药性癫痫大鼠GABAA受体表达中发挥重要作用。本研究有望对癫痫耐药机制提供新的理论依据，同时可能发现新的药物治疗靶点。

Patients with pharmacoresistant epilepsy displayed significant decreased GABAA receptors in the focal brain tissues. However, the mechanisms underlying the decrease of the GABAA receptors are unclear. The cAMP response element binding protein(CREB) decreased remarkably in the brain of the epileptic rats and the patients with intractable epilepsy. It is speculated that consistent activation of the CREB in the focal brain tissues leads to the decreased expression of the GABAA receptors. Therefore, the antiepileptic drugs fail to control the epilepsy. The present study aims to explore the molecular mechanism underlying the decreased GABAA receptors in the brain of pharmacoresistant epileptic rats. We will firstly prepare the model of pharmacoresistant epileptic rats. And then, the techniques of gene modulation, signal pathway activation or blocking are used to modulate the CREB function. Subsequently, the expression of the GABAA receptors, the epileptic seizures and the amygdalae EEGs are to be observed. The IPSC、mIPS and the membrane excitability of the hippocapal neurons are to be recorded. The technique of chromatin immunoprecipitation is used to observe the combination of the CREB and the GABAA receptors. These studies might be helpful in demonstrating that if the CREB play important roles in decreasing the GABAA receptors of the pharmacoresistant epileptic rats. The present studies are expected to provide theoretical evidences for the pharmacoresistant mechanism of epilepsy, and probably to discover the new target of antiepileptic drugs in the treatment of pharmacoresistant epilepsy.