CREB and Synaptic Reorganization

描述（由申请人提供）：癫痫发作诱导的突触结构改变可能是某些形式癫痫发生的潜在机制。特别突出的是颞叶癫痫患者齿状回苔藓纤维连接的重塑。过度的兴奋性神经传递引发了什么样的信号事件，从而触发了齿状回的突触重组？虽然这一过程背后的细胞事件没有得到很好的表征，但用于产生苔藓纤维发芽（和复发性癫痫发作）的范例与用于产生长期神经元可塑性的范例的相似性提高了相同的细胞内信号传导途径构成这些不同生理过程的基础的可能性。因此，我们建议检查是否通过CREB/CRE转录通路的信号传导耦合颞叶癫痫苔藓纤维发芽。对这种可塑性相关转录途径的兴趣也来自我们的初步数据，这些数据显示癫痫发作触发CREB/CRE途径的激活，并且激活的CREB的过度表达导致神经突生长。因此，我们假设癫痫发作触发CREB/CRE通路激活，这反过来又驱动了苔藓纤维发芽基因的表达。目的1将确定在齿状回中，姜黄素诱导的CREB激活和CREB介导的转录的时间分布。从癫痫发作开始，通过静默期，一直到复发性癫痫发作期间，将监测激活。调节转录因子和上游激酶的作用也将被检查。在目标2中，我们将调查CRE-dependent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作为癫痫发作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引起的认知缺陷是否与CREB/CRE转录途径的异常调节有关。了解将癫痫发作与突触重塑相结合的细胞内信号传导事件，应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.