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 一系列具有显著健康和生活质量影响的相关合并症， 国家科学院赞助的公共卫生方面委员会强调， 癫痫。1我们的研究实验室已经产生了实验性发热状态的啮齿动物模型 癫痫发作（eFSE），它引起颞叶癫痫样发作和认知缺陷，从而 提供了一个强有力的工具来探测这些条件下的机制。在eFSE之后，大鼠表现出 在主动回避测试（一种空间认知测试）中存在显著缺陷， 振荡活动和异常的时间编码的动作电位相比，控制。最近， 我们确定了一些潜在的癫痫促进海马功能变化的机制， 由EFSE引发的网络。具体来说，我们观察到协调转录调控的变化， 多个基因的表达控制神经元的行为，这是由于eFSE诱导上调 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可以预防认知功能障碍和神经元失调 癫痫持续状态之后虽然我们的研究结果的治疗意义是令人兴奋的， EFSE诱导的异常NRSF活动如何导致基因表达和成熟的破坏， 特定的细胞群体在整个电路受到eFSE的影响。该提案旨在确定生物 在分子、单细胞和电路水平上，eFSE诱导的认知缺陷的基础， 确定NRSF阻断如何逆转这些缺陷。此外，我们将确定NRSF是否参与了 与其他发育性癫痫发作相关的记忆问题，因为这将是我们翻译的必要条件。 发现。拟议的多学科、多层面和尖端实验将解决以下问题： 参与eFSE诱导的记忆障碍的机制，并建立如何逆转这种疾病 通过遗传方法。这些研究也将为记忆回路的机制提供新的见解 成熟，并对大量患有发热性癫痫持续状态的儿童有潜在的重大影响。

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.