CREB and Synaptic Reorganization

描述（由申请人提供）：癫痫引起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体苔藓纤维连接的重塑。过度兴奋性神经传递引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尚未被很好地描述，但用于产生苔藓纤维发芽（和复发性癫痫发作）和用于产生长期神经元可塑性的范式的相似性提出了一种可能性，即相同的一组细胞内信号通路是这些不同生理过程背后的基础。因此，我们建议研究通过CREB/CRE转录途径的信号传导是否将颞叶癫痫与苔藓纤维发芽联系起来。我们对这种可塑性相关转录途径的兴趣也来自于我们的初步数据，这些数据表明癫痫发作会触发CREB/CRE通路的激活，而激活的CREB的过度表达会导致强劲的神经突生长。因此，我们假设癫痫发作触发CREB/CRE通路激活，进而驱动负责苔藓纤维发芽的基因表达。在Aim 1中，将确定癫痫诱发的CREB激活和CREB介导的齿状体转录的时间谱。激活将被监测从癫痫发作，通过沉默期，并进入反复发作期。调节转录因子和上游激酶的作用也将被检查。在目标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，我们将研究CREB调节的细胞存活和可塑性基因的表达模式，并研究CREB作为癫痫诱导的神经元前体细胞分化的调节剂的作用。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。了解将癫痫发作与突触重构相结合的细胞内信号事件，将有助于开发旨在阻断某些形式癫痫发展的治疗方法。

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.