GABA (A) Receptor Subunit Regulation in Epileptogenesis

描述（由申请人提供）：颞叶癫痫（TLE）是最常见的癫痫形式，通常是医学上难以治愈的。大量证据表明抑制性神经传递异常在TLE中起重要作用。GABAA受体（GABARs）是前脑中最丰富的抑制性神经递质受体，然而，关于其在健康或疾病中的表达调控相对知之甚少。我们已经证明，在成年大鼠癫痫持续状态（SE）后，海马齿状颗粒神经元（DGN）中GABAR亚单位表达的长期变化，包括α 1亚单位的减少，与受体药理学和功能的显著变化相关。此外，a1的变化高度依赖于SE发生的年龄，并且与随后癫痫发展的可能性成反比。此外，我们发现使用病毒介导的基因转移增强a1水平抑制SE后癫痫的发展。这些研究结果表明，减少a1水平的DGN可能有助于癫痫的发生和a1水平升高可能是保护性的。然而，要利用这种治疗潜力，需要了解GABAR α 1亚基的表达是如何调节的。因此，我们建议调查潜在的调控机制，控制GABAR α 1基因的表达。我们将研究两个确定的候选信号通路，cAMP反应元件结合蛋白（CREB）通路和糖皮质激素受体通路，在调节GABAR α 1亚基表达SE后的作用。此外，使用生物信息学和蛋白质组学的组合，我们将进行其他转录因子的筛选，显示增强的相互作用与a1启动子后SE。这些研究有望阐明a1的表达是如何调节的，以及这种调节在癫痫发生过程中是如何改变的。这些研究的结果将有助于开发新的治疗方法，通过确定潜在的新的治疗靶点，特别是针对GABAR亚基基因表达的调控，用于预防或治疗癫痫。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common form of epilepsy and is frequently medically intractable. There is abundant evidence that abnormalities in inhibitory neurotransmission play an important role in TLE. GABAA receptors (GABARs) are the most abundant inhibitory neurotransmitter receptors in forebrain, however, relatively little is known regarding regulation of their expression either in health or in disease. We have demonstrated long-term changes in expression of GABAR subunits, including decreases in the a1 subunit, in hippocampal dentate granule neurons (DGNs) following status epilepticus (SE) in adult rats, that are associated with marked changes in receptor pharmacology and function. Further, changes in a1 are highly dependent on the age at which SE occurs, and vary inversely with the likelihood of subsequent epilepsy development. In addition, we find that enhancing a1 levels using viral mediated gene transfer inhibits development of epilepsy after SE. These findings suggest that diminished a1 levels in DGN may contribute to epileptogenesis and that elevated a1 levels could be protective. To utilize this therapeutic potential, however, requires an understanding of how GABAR a1 subunit expression is regulated. We therefore propose to investigate potential regulatory mechanisms that control GABAR a1 gene expression. We will examine the role of two identified candidate signaling pathways, the cAMP response element binding protein (CREB) pathway and the glucocorticoid receptor pathway, in regulating GABAR a1 subunit expression following SE. Further, using a combination of bioinformatics and proteomics we will perform a screen for other transcription factors that show enhanced interaction with the a1 promoter after SE. The proposed studies are expected to elucidate how a1 expression is regulated and how this regulation is altered during epileptogenesis. Results of these studies should facilitate development of new therapies for the prevention or cure of epilepsy by identifying potential new therapeutic targets that specifically target regulation of GABAR subunit gene expression.