CREB and Synaptic Reorganization

CREB ​​和突触重组

• 批准号: 6867214
• 负责人: KARL H OBRIETAN
• 金额: $ 29.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867214
• 关键词: behavioral genetics; biological signal transduction; cAMP response element binding protein; dentate gyrus; epilepsy; gene expression; genetic transcription; genetically modified animals; granule cell; laboratory mouse; laboratory rat; mossy fiber; neural plasticity; neural transmission; neuronal guidance; neuroregulation; newborn animals; phosphorylation; pilocarpine; synaptogenesis; tissue /cell culture

DESCRIPTION (provided by applicant): Seizure-induced alterations in synaptic architecture may be an underlying mechanism in the development of some forms of epilepsy. Of particular prominence is the remodeling of dentate gyms mossy fiber connections in patients with temporal lobe epilepsy. What are the signaling events elicited by excessive excitatory neurotransmission that trigger synaptic reorganization in the dentate gyrus? Although the cellular events that underlie this process are not well characterized, the similarities in the paradigms used to produce mossy fiber sprouting (and recurrent seizures) and those used to produce long-term neuronal plasticity raise the possibility that the same set of intracellular signaling pathways underlie these distinct physiological processes. Thus, we propose to examine whether signaling via the CREB/CRE transcriptional pathway couples temporal lobe seizures to mossy fiber sprouting. Interest in this plasticity-associated transcriptional pathway also comes from our preliminary data showing that seizures trigger activation of the CREB/CRE pathway, and that over-expression of activated CREB leads to robust neurite outgrowth. Thus, we hypothesize that seizures trigger CREB/CRE pathway activation, which in turn drives the expression of genes responsible for mossy fiber sprouting. In Aim 1 will determine the temporal profile of seizure-induced CREB activation and CRE-mediated transcription in the dentate gyms. Activation will be monitored from seizure onset, through the silent period, and on into the period of recurrent seizures. The role of modulatory transcription factors and upstream kinases will also be examined. In Aim 2 we will investigate the causal relationship between CRE-dependent transcription and mossy fiber sprouting. In Aim 3 we will examine the expression pattern of CREB-regulated cell survival and plasticity genes and examine the role of CREB as a regulator of seizure induced neuronal precursor cell differentiation. We will also determine whether cognitive deficits resulting from status epilepticus are associated with aberrant regulation of the CREB/CRE transcriptional pathway. An understanding of the intracellular signaling events that couple seizures to synaptic remodeling should allow for the development of therapeutic approaches designed to block the development of some forms of epilepsy.

描述（由申请人提供）：癫痫发作的突触体系结构的改变可能是某些形式的癫痫发展的基本机制。特别突出的是颞叶癫痫患者的齿状体育体苔藓纤维连接的重塑。过量的兴奋性神经传递引起了什么信号事件，这些神经传递会触发齿状回的突触重组？尽管该过程构成的细胞事件没有很好地表征，但是用于产生苔藓纤维发芽（和经常性癫痫发作）的范例中的相似性，以及用于产生长期神经可塑性的相似之处增加了相同的一组细胞内信号途径的可能性，这是这些独特的物理过程的基础。因此，我们建议检查是否通过CREB/CRE转录途径发出信号伴侣颞叶癫痫发作至苔藓纤维发芽。对这种可塑性相关的转录途径的兴趣也来自我们的初步数据，表明癫痫发作触发了CREB/CRE途径的激活，并且激活的CREB的过表达导致了强大的神经突生物的生长。因此，我们假设癫痫发作会触发CREB/CRE途径激活，这反过来驱动了负责苔藓纤维发芽的基因的表达。在AIM 1中，将确定癫痫发作诱导的CREB激活和CRE介导的转录的时间分布。将从癫痫发作，到静默时期，再到复发性癫痫发作时期监测激活。还将检查调节转录因子和上游激酶的作用。在AIM 2中，我们将研究CRE依赖性转录与苔藓纤维发芽之间的因果关系。在AIM 3中，我们将检查CREB调节的细胞存活和可塑性基因的表达模式，并检查CREB作为癫痫发作诱导的神经元前体细胞分化的作用。我们还将确定由状态癫痫持续药引起的认知缺陷是否与CREB/CRE转录途径的异常调节有关。对持续癫痫发作的细胞内信号传导事件的理解应允许开发旨在阻止某些形式的癫痫发育的治疗方法。