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)：癫痫诱发的突触结构改变可能是某些形式癫痫发展的潜在机制。特别突出的是颞叶癫痫患者齿状回苔藓状纤维连接的重塑。过度的兴奋性神经传递触发齿状回突触重组的信号事件是什么？尽管这一过程背后的细胞事件没有得到很好的描述，但用于产生苔藓状纤维发芽(和反复发作)的范例与用于产生长期神经元可塑性的范例的相似性增加了这样一种可能性，即相同的一套细胞内信号通路是这些不同生理过程的基础。因此，我们建议研究通过CREB/Cre转录途径的信号是否将颞叶癫痫发作与苔藓纤维发芽联系起来。对这一可塑性相关转录途径的兴趣也来自我们的初步数据，即癫痫发作触发CREB/CRE途径的激活，激活的CREB的过度表达导致强大的轴突生长。因此，我们假设癫痫发作触发了CREB/CRE途径的激活，这反过来又驱动了负责苔藓纤维发芽的基因的表达。在Aim 1中，将确定癫痫诱导的CREB激活和Cre介导的齿状回转录的时间分布。将监测从癫痫发作开始，到静止期，直到反复癫痫发作期间的激活情况。调节转录因子和上游激酶的作用也将被研究。在目标2中，我们将研究依赖于Cre的转录和苔藓纤维发芽之间的因果关系。在目标3中，我们将研究CREB调控的细胞存活和可塑性基因的表达模式，并研究CREB在癫痫诱导的神经前体细胞分化中的调节作用。我们还将确定癫痫持续状态导致的认知缺陷是否与CREB/CRE转录途径的异常调节有关。对将癫痫发作与突触重塑联系在一起的细胞内信号事件的了解，应该有助于开发旨在阻止某些形式癫痫的发展的治疗方法。