BDNF and JAK/STAT: partners in seizure-induced GABA-A receptor downregulation

癫痫是一种以反复发作为特征的神经系统疾病，影响全世界5000多万人。颞叶癫痫（TLE）是一种常见的癫痫形式，癫痫发作源于颞叶。TLE可能会使人衰弱，因为许多患者会经历记忆功能受损和抑郁，或者由于意识丧失而遭受与癫痫相关的伤害。此外，每年有多达5万人死于癫痫发作和相关原因。由于这种潜在的严重健康风险，了解TLE背后的分子机制以更好地治疗这种疾病是很重要的。癫痫神经元在癫痫发作期间表现出明显的活动，由包括3-氨基丁酸（GABA）在内的神经递质控制。A型GABA受体组成的改变可能与癫痫易感性有关。特别是，在人类和TLE动物模型中观察到长时间癫痫发作后14个亚基上调和11个亚基下调。我们的实验室已经确定脑源性神经营养因子（BDNF）是通过激活Janus激酶(JAK)/信号转导和转录激活因子（STAT）途径介导下调的关键调节剂，该途径控制诱导型cAMP早期抑制因子（ICER）的表达。我们的一般假设是BDNF信号通过JAK/STAT通路下调癫痫持续状态（SE）后11的表达，导致抑制功能受损，这在癫痫发生过程中起关键作用。使用多种技术，包括培养和体内基因沉默、染色质免疫沉淀（ChIP）和蛋白/蛋白相互作用的共免疫沉淀，将确定由BDNF的前期或成熟形式激活的JAK/STAT信号通路的特定组分。我们还将确定神经营养因子受体TrkB和p75NTR与JAK/STAT复合物是否存在直接关联，以及在匹罗卡品TLE模型中JAK/STAT激活对癫痫发生的潜在作用。这些研究为直接识别由SE激活的BDNF诱导的JAK/STAT通路的不同成员奠定了基础，有望为未来治疗难治性癫痫以及其他显示11亚基表达降低的疾病提供新的治疗靶点。

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting more than 50 million people worldwide. Temporal lobe epilepsy (TLE) is a common form of epilepsy, where seizures arise from the temporal lobe. TLE can be debilitating, as many patients experience impaired memory function and depression, or suffer seizure-related injuries due to loss of consciousness. Furthermore, up to 50,000 people die each year from seizures and related causes. With the potential for such serious health risks it is important to understand the molecular mechanisms behind TLE to better treat the disorder. Epileptic neurons exhibit distinct activity during seizures, controlled by neurotransmitters including 3-aminobutyric acid (GABA). Altered type A GABA receptor composition may contribute to seizure susceptibility. In particular, an upregulation of 14 and a downregulation of 11 subunits are observed after prolonged seizures in humans and in TLE animal models. Our laboratory has identified brain derived neurotrophic factor (BDNF) as a key regulator that mediates 11 downregulation through its activation of the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway, that controls expression of inducible cAMP early repressor (ICER). Our general hypothesis is that BDNF signals through the JAK/STAT pathway to downregulate 11 expression after status epilepticus (SE), resulting in impaired inhibition that plays a critical role in the process of epileptogenesis. Using a variety of techniques including gene silencing in culture and in vivo, chromatin immunoprecipitation (ChIP), and co-immunoprecipitation of protein/protein interactions, specific components of the JAK/STAT signaling pathway activated by either the pro- or mature forms of BDNF will be identified. We will also determine whether there is a direct association of neurotrophin receptors TrkB and p75NTR with the JAK/STAT complex, as well as the potential role of JAK/STAT activation to epileptogenesis in the pilocarpine TLE model. The proposed studies lay the foundation for directly identifying distinct members of the BDNF- induced JAK/STAT pathway activated by SE, with the promise of providing novel therapeutic targets for future treatment of intractable epilepsy as well as other disorders that display reduced 11 subunit expression.