GABA (A) Receptor Subunit Regulation in Epileptogenesis

颞叶癫痫（TLE）是最常见的癫痫形式，并且通常是医学上难治的。 大量证据表明抑制性神经传递异常在TLE中起重要作用。 GABA（A）受体（GABARs）是前脑中最丰富的抑制性神经递质受体， 然而，关于它们在健康或疾病中表达的调节知之甚少。我们 已经证实GABAR亚单位表达的长期变化，包括c1 成年大鼠癫痫持续状态（SE）后海马齿状核神经元（DGN）中的一个亚单位， 与受体药理学和功能的显著变化有关。此外，a1水平的变化 高度依赖于SE发生的年龄，并与随后发生的可能性成反比。 癫痫发展此外，我们发现，使用病毒介导的基因增强a1亚基水平， 转移抑制SE后癫痫的发展。这些发现表明，在糖尿病性肾小球肾炎中， 可能有助于癫痫的发生，升高的A1水平可能具有保护作用。利用这种治疗方法 潜在的需要了解GABAR α 1亚基基因（GABRA1）是如何调节的。我们 因此，建议研究控制GABRA1表达的潜在调控机制。我们将 研究了两个已确定的候选信号通路的作用，cAMP反应元件结合蛋白 （CREB）通路和糖皮质激素受体通路，在SE后调节GABRA 1。此外，本发明还 使用蛋白质组学技术，我们将确定与转录因子相互作用的转录因子的星座。 GABRA1启动子在CREB和GR的共同位点区域中的位置，并确定该星座是否 SE后的变化。这些拟议的研究有望阐明控制GABRA1的机制。 表达，并确定如何在癫痫发生过程中改变这种调节。这些研究结果 应通过识别潜在的癫痫，促进新疗法的开发， 特异性调节GABAR亚基基因表达的新治疗靶点。 与公共卫生的相关性：癫痫影响着250多万美国人。严重的癫痫发作， 在高达20%的癫痫患者中发生抵抗治疗，并且可能与寿命缩短有关， 社会和智力障碍、就业不足和生活质量下降。拟议的研究 应该确定癫痫发作后参与神经细胞传递的关键基因的表达是如何调节的 并可能导致新的和更好的方法来治疗或预防癫痫。

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. GABA(A) 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 thecc1 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 levels 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 subunit levels using viral mediated gene transfer inhibits development of epilepsy after SE. These findings suggest that diminished cc1levels in DGN may contribute to epileptogenesis and that elevated a1 levels could be protective. To utilize this therapeutic potential requires an understanding of how the GABAR a1 subunit gene (GABRA1) is regulated. We therefore propose to investigate potential regulatory mechanisms that control GABRA1 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 GABRA1 following SE. Further, using proteomics techniques we will identify the constellation of transcription factors that interact with the GABRA1 promoter in the region of concensus sites for CREB and GRs and determine if this constellation changes after SE. The proposed studies are expected to elucidate mechanisms that control GABRA1 expression and determine 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 regulate GABAR subunit gene expression. Relevance to Public Health: Epilepsy affects more than 2.5 million Americans. Severe seizures that resist treatment occur in up to 20% of epilepsy patients and can be associated with a shortened life span, social and intellectual impairment, underemployment and a reduced quality of life. The proposed studies should identify how expression of key genes involved in nerve cell transmission are regulated after seizures and may lead to new and better ways to treat or prevent epilepsy.