Cognitive Deficits After Experimental Febrile Seizures: Neurobiology & Biomarkers

描述（由申请人提供）：热性惊厥是幼儿中最常见的癫痫发作类型。不幸的是，一些长期高热惊厥的儿童似乎有长期认知障碍的风险。识别那些有认知障碍风险的个体并发现负责任的机制将为治疗干预提供机会。在通过R21资助机制进行的初步研究中，我们使用了一种长期实验性热性惊厥（EFS）的未成熟大鼠模型，并确定了一个亚组的大鼠在成年期出现了空间记忆障碍和异常的位置细胞功能。癫痫发作一个月后，海马依赖性空间认知的这些缺陷伴随着海马MRI T2信号升高。这些发现首次证明了EFS对控制记忆表现的特定神经元功能的直接因果效应，表明MRI可能是认知障碍风险个体的潜在预测生物标志物。此外，我们发现，MRI T2信号在海马癫痫发作后一个月与炎症激活，但没有明显的细胞死亡，表明炎症介质可能有助于MRI异常和神经元功能障碍，提供了一个目标，选择性干预。然而，在将这些发现应用于FSE儿童的管理之前，还需要更多的关键信息。目前尚不清楚海马MRI变化是否发生得足够早，以预测认知缺陷，因此可用于潜在的干预，或者观察到的细胞和认知障碍是否是FSE或随后癫痫发生的结果。确定是否海马水平的炎性细胞因子白细胞介素（IL）-12区分FSE大鼠，成为癫痫从那些谁没有，如果这种细胞因子是参与由EFS引起的认知缺陷是必要的。在这项提案中，我们将评估是否在一个子集的大鼠经历FSE的认知缺陷预测的选择性MRI变化是可见的癫痫发作后的早期和FSE后出现的认知和位置细胞缺陷之前，并独立于癫痫过程和自发性癫痫发作，并定义这种缺陷的潜在机制。为了确定炎症细胞因子的表达是否区分FSE后认知缺陷的大鼠与那些完整的记忆依赖性记忆，我们将比较EFS后有和没有细胞因子变化的大鼠。这项研究的结果将为热性惊厥后有认知问题风险的儿童的治疗干预奠定基础。

DESCRIPTION (provided by applicant): Febrile seizures are the most common type of seizure seen in young children. Unfortunately, some children with prolonged febrile seizures appear to be at risk for long-term cognitive disturbances. Identifying those individuals at risk for cognitive impairment and discovering the responsible mechanisms would provide opportunities for therapeutic intervention. In preliminary studies through an R21 funding mechanism, we used an immature rat model of long experimental febrile seizures (EFS) and established that a subgroup of rats experiencing these seizures developed spatial memory impairment and aberrant place cell function during adulthood. These deficits in hippocampal-dependent spatial cognition were accompanied by elevated MRI T2 signals in the hippocampus one month after the seizures. These findings demonstrate for the first time a direct causal effect of EFS on function of specific neurons that govern memory performance suggesting that MRI might be a potentially predictive biomarker for individuals at risk for cognitive disturbances. Furthermore, we have found that MRI T2 signals in hippocampus one month after the seizures are associated with inflammatory activation but no overt cell death indicating that inflammatory mediators might contribute to both MRI abnormalities and neuronal dysfunction, providing a target for selective intervention. However, prior to the application of these findings to the management of children with FSE additional critical information is needed. It is not known if hippocampal MRI changes take place early enough to be predictive of cognitive defects, and thus useful for potential intervention or whether the observed cellular and cognitive impairments are result of the FSE or of ensuing epileptogenesis. Determining if hippocampal levels of the inflammatory cytokine interleukin (IL)-12 distinguish FSE rats that became epileptic from those who did not and if this cytokine is involved in the cognitive defects provoked by EFS is necessary. In this proposal we will assess whether the cognitive defects in a subset of rats experiencing FSE are predicted by selective MRI changes that are visible early after the seizures and whether the cognitive and place-cell defects after FSE emerge prior to, and independent from, the epileptogenic process and spontaneous seizures, and define the underlying mechanisms of such deficits. To ascertain whether inflammatory cytokine expression distinguishes rats with cognitive defects after FSE from those with intact hippocampus-dependent memory we will compare rats with and without cytokine changes after EFS. The results of this study will set the stage for therapeutic intervention in children at risk for cognitive problems following febrile seizures.