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发病中起重要作用。GABAA受体是由来自多个亚基家族的亚基组成的五聚体，表现出发育、地区和疾病特异性的表达差异，然而，对其在健康或疾病中的调控知之甚少。我们的实验室已经确定了GABAR a亚单位基因表达的长期变化，包括癫痫持续状态(SE)后大鼠海马齿状回颗粒神经元A1基因(Gabra1)表达的减少，这与癫痫的后期发展有关。在以前的资金支持阶段，我们证实了SE后Gabra1转录减少是由可诱导的cAMP早期抑制因子(ICER)和与Gabra1 Cre位点结合的磷酸化CREB介导的。我们进一步证明，ICER的转录是由Janus Kinase(JAK)/Signal Transducer(Jenus Kinase/Signal Transducer)信号转导和转录激活因子(Activator of Transcription，STAT)信号级联激活的，通过脑源性神经营养因子(BDNF)的作用。JAK/STAT通路在癫痫中的研究很少，除了它在Gabra1调节中的作用外，它还被认为是神经元增殖、存活和神经胶质形成的重要调节因子，所有这些都可能是癫痫发生的重要因素。在目前的提案中，我们将研究BDNF如何通过JAK/STAT通路控制大脑中GABAR亚单位的表达，以及它在癫痫易感性中的潜在作用。具体地说，我们建议：1.确定BDNF如何激活JAK/STAT通路。II.确定SE后体内JAK/STAT活化的区域和细胞特异性。III.确定SE前后是否可以通过操纵BDNF诱导的JAK/STAT通路将动物从癫痫发展中解救出来。这些研究的结果将提供关于BDNF和JAK/STAT信号级联在其脑抑制调节中的动态相互作用的新信息，特别是当它与含有A1的GABARs的形成有关时，并有望促进预防、治疗或治疗癫痫以及其他神经系统疾病的新疗法的开发，这些疾病分享含有A1的GABARs的功能表达的变化。 公共卫生相关性：癫痫和癫痫发作影响着300多万美国所有年龄段的人，以及全世界5000万人。超过30%的癫痫患者有目前的治疗无法控制的癫痫发作，每年多达5万人死于癫痫发作和相关原因。拟议中的研究试图通过识别并逆转导致这种情况的脑细胞变化来寻找治疗和预防癫痫的新方法。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common form of epilepsy & is often medically intractable. A large body of evidence indicates that abnormalities in inhibitory neurotransmission play an important role in TLE. GABAA receptors (GABARs) are pentamers composed of subunits from multiple subunit families that display developmental, regional and disease specific differences in expression, however, little is known regarding their regulation either in health or in disease. Our laboratories have identified long-term changes in GABAR a subunit gene expression, including decreases in expression of the a1 gene (Gabra1) in rat hippocampal dentate granule neurons following status epilepticus (SE) that are associated with later development of epilepsy. In the previous funding period, we established that decreased transcription of Gabra1 after SE is mediated by inducible cAMP early repressor (ICER) and phosphorylated CREB that bind to the Gabra1 CRE site. We further showed that ICER transcription is activated by the Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling cascade, via actions of brain derived neurotrophic factor (BDNF). The JAK/STAT pathway has been little studied in epilepsy, and beyond its role in Gabra1 regulation, it is known to be an important regulator of neuronal proliferation, survival and gliogenesis, all of which may be important contributors to epileptogenesis. In the current proposal we will examine how BDNF signals through the JAK/STAT pathway to control GABAR subunit expression in the brain and its potential role in seizure- susceptibility. Specifically, we propose to: I. Determine how BDNF activates the JAK/STAT pathway. II. Determine the region and cell specificity of JAK/STAT activation in vivo after SE. III. Determine whether animals can be rescued from epilepsy development via manipulation of the BDNF-induced JAK/STAT pathway before or after SE. Results of these studies will provide new information about the dynamic interactions of BDNF and the JAK/STAT signaling cascade in its regulation of brain inhibition, especially as it pertains to the formation of a1 containing GABARs, and have the promise of facilitating the development of new therapies for the prevention, treatment or cure of epilepsy, as well as other nervous system disorders that share a change in the functional expression of a1 containing GABARs. PUBLIC HEALTH RELEVANCE: Epilepsy and seizures affect over 3 million Americans of all ages, and 50,000,000 people worldwide. Over thirty percent of patients with epilepsy have seizures that cannot be controlled with current treatments and up to 50,000 people die each year from seizures and related causes. The proposed studies seek to find new ways of treating and preventing epilepsy by identifying and then reversing the changes in brain cells that lead to this condition.