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，通常是医学难治性的。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（gabar）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的研究相对较少。我们已经证明了成年大鼠癫痫持续状态（SE）后海马齿状颗粒神经元（DGNs）中GABAR亚基的长期表达变化，包括a1亚基的减少，这与受体药理学和功能的显着变化有关。此外，a1的变化高度依赖于SE发生的年龄，并与随后癫痫发展的可能性成反比。此外，我们发现通过病毒介导的基因转移提高a1水平可以抑制SE后癫痫的发展。这些发现表明，DGN中a1水平的降低可能有助于癫痫发生，而a1水平的升高可能具有保护作用。然而，为了利用这种治疗潜力，需要了解GABAR a1亚基表达是如何被调节的。因此，我们建议研究控制GABAR a1基因表达的潜在调控机制。我们将研究两个已确定的候选信号通路，cAMP反应元件结合蛋白（CREB）途径和糖皮质激素受体途径，在SE后调节GABAR a1亚基表达中的作用。此外，结合生物信息学和蛋白质组学，我们将筛选SE后与a1启动子相互作用增强的其他转录因子。拟议的研究有望阐明在癫痫发生过程中如何调节a1的表达以及这种调节是如何改变的。这些研究的结果应该通过确定特异性靶向GABAR亚基基因表达调控的潜在新治疗靶点，促进预防或治愈癫痫的新疗法的开发。

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.