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，通常在医学上难以治疗。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）是由来自多个亚基家族的亚基组成的五聚体，它们在表达上表现出发育、区域和疾病特异性差异，然而，人们对它们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a1基因（Gabra1）表达的减少，这与癫痫的后期发展有关。在之前的资助期内，我们确定了SE后Gabra1的转录减少是由诱导性cAMP早期抑制因子（ICER）和与Gabra1 CRE位点结合的磷酸化CREB介导的。我们进一步发现，通过脑源性神经营养因子（BDNF）的作用，Janus Kinase (JAK)/Signal transducator and Activator of transcription （STAT）信号级联可激活ICER转录。JAK/STAT通路在癫痫中的研究很少，除了在Gabra1调节中的作用外，它还被认为是神经元增殖、存活和胶质瘤发生的重要调节因子，所有这些都可能是癫痫发生的重要因素。在当前的提案中，我们将研究BDNF信号如何通过JAK/STAT途径控制GABAR亚基在大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：1 .确定BDNF如何激活JAK/STAT通路。2。测定SE后体内JAK/STAT激活的区域和细胞特异性。3。确定是否可以通过操纵bdnf诱导的JAK/STAT通路在SE之前或之后从癫痫发展中拯救动物。这些研究的结果将为BDNF和JAK/STAT信号级联在脑抑制调控中的动态相互作用提供新的信息，特别是当它与含有a1的gabar的形成有关时，并有希望促进预防、治疗或治愈癫痫的新疗法的开发，以及其他神经系统疾病，这些疾病共享含有a1的gabar的功能表达变化。

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. 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.