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）是由来自多个亚基家族的亚基组成的五聚体，其在表达上显示发育、区域和疾病特异性差异，然而，关于其在健康或疾病中的调节知之甚少。我们的实验室已经确定了GABAR a亚基基因表达的长期变化，包括癫痫持续状态（SE）后大鼠海马齿状颗粒神经元中a1基因（Gabra 1）表达的减少，这与癫痫的后期发展有关。在之前的资助期间，我们确定SE后Gabra 1的转录减少是由可诱导的cAMP早期阻遏物（ICER）和磷酸化的CREB介导的，这些CREB与Gabra 1 CRE位点结合。我们进一步表明，ICER转录是由Janus激酶（JAK）/信号转导和转录激活因子（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，除了其在Gabra 1调节中的作用外，已知它是神经元增殖、存活和胶质细胞生成的重要调节剂，所有这些都可能是癫痫发生的重要贡献者。在目前的建议中，我们将研究BDNF如何通过JAK/STAT信号通路来控制GABAR亚基在脑中的表达及其在癫痫易感性中的潜在作用。具体而言，我们建议：确定BDNF如何激活JAK/STAT通路。二.确定SE后体内JAK/STAT激活的区域和细胞特异性。三.确定动物是否可以通过在SE之前或之后操纵BDNF诱导的JAK/STAT通路从癫痫发展中拯救出来。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，特别是因为它涉及含有α 1的GABAR的形成，并且有希望促进用于预防、治疗或治愈癫痫的新疗法的开发，以及其它神经系统疾病，其共享含α 1的GABAR的功能表达的变化。

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.