Cognitive Deficits After Experimental Febrile Seizures: Neurobiology & Biomarkers

项目摘要 癫痫是一种复杂的疾病，涉及的不仅仅是癫痫发作。它也可能伴随着一个 具有重大健康和生活质量影响的相关并存健康状况的范围如下 由国家科学院赞助的公共卫生问题委员会强调 1.我们的研究实验室已经建立了一个实验性发热状态的啮齿动物模型 癫痫(EFSE)，引起颞叶癫痫样发作和认知障碍，从而 为探索这些疾病背后的机制提供了一个强大的工具。在EFSE之后，老鼠展示了 主动回避测试--一种空间认知测试--的显著缺陷，并显示出海马区的改变 与对照组相比，动作电位的振荡活动和时间编码异常。最近， 我们确定了一些促进癫痫的海马区功能变化的机制。 EFSE挑起的网络。具体地说，我们观察到在转录调控的协调变化 EFSE诱导的神经元行为调控基因的表达上调 神经元限制性沉默因子(NRSF)的表达和功能值得注意的是，我们的初步研究 提示阻断NRSF可以预防认知障碍和神经元的不协调。 紧随癫痫持续状态。虽然我们发现的治疗意义是令人兴奋的，但尚不清楚 EFSE诱导的NRSF活性异常如何影响基因表达和成熟度 受EFSE影响的整个回路中的特定细胞群。这项建议旨在确定生物 EFSE诱导的分子、单细胞和电路水平的认知缺陷的基础，以及 确定NRSF-封锁如何扭转这些赤字。此外，我们将确定NRSF是否参与了 与其他发育性癫痫相关的记忆问题，因为这将是翻译我们的 发现。拟议的多学科、多维度和尖端实验将解决 EFSE诱导记忆障碍的机制，并确定如何逆转这种障碍 通过遗传方法。这些研究也将为记忆-电路的机制提供新的见解 这可能对大量患有发热性癫痫持续状态的儿童产生潜在的重大影响。

Project Summary Epilepsy is a complex disorder which involves much more than seizures. It may also be accompanied by a range of associated comorbid health conditions with significant health and quality of life implications as emphasized by the National Academy of Science-sponsored Committee on the Public Health Dimensions of the Epilepsies.1 Our research laboratories have generated a rodent model of experimental febrile status epilepticus (eFSE), which provokes both temporal lobe epilepsy-like seizures and cognitive deficits, thereby providing a powerful tool to probe the mechanisms underlying these conditions. Following eFSE, rats exhibit significant deficits in the active avoidance test—a test of spatial cognition—and show altered hippocampal oscillatory activity and abnormal temporal coding of action potentials when compared with controls. Recently, we identified some of the mechanisms underlying epilepsy-promoting functional changes in the hippocampal network provoked by eFSE. Specifically, we observed coordinated transcriptionally-regulated changes in the expression of multiple genes governing neuronal behavior which resulted from eFSE-induced up-regulated expression and function of the neuron-restrictive silencing factor (NRSF). Remarkably, our preliminary studies indicate that both the cognitive deficits and the neuronal discoordination can be prevented by blocking NRSF following status epilepticus. While the therapeutic implications of our findings are exciting, it is not yet known how eFSE-induced abnormal NRSF activities contribute to disruption of gene expression and maturation of specific cell populations throughout the circuit affected by eFSE. This proposal aims to determine the biological underpinnings of eFSE-induced cognitive deficits at the molecular, single cell and circuit levels, and to establish how NRSF-blockade reverses these deficits. In addition, we will determine if NRSF is involved in memory problems associated with other developmental seizures as this will be a requisite for translation of our discoveries. The proposed multidisciplinary, multidimensional and cutting-edge experiments will address the mechanisms involved in eFSE-induced memory disorders and establish how such disorders can be reversed through genetic methods. These studies will also provide novel insights into mechanisms of memory-circuit maturation and have a potential major impact on a large population of children with febrile status epilepticus.