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惊厥类型。不幸的是，一些长时间发热性癫痫发作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相关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，我们使用了长时间实验性热性惊厥（EFS）的未成熟大鼠模型，并确定经历这些惊厥的大鼠亚群在成年期出现空间记忆障碍和异常的位置细胞功能。这些海马依赖空间认知的缺陷在癫痫发作一个月后伴随着海马MRI T2信号的升高。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影响，这表明MRI可能是一种潜在的预测认知障碍风险个体的生物标志物。此外，我们发现癫痫发作一个月后海马的MRI T2信号与炎症激活有关，但没有明显的细胞死亡，这表明炎症介质可能导致MRI异常和神经元功能障碍，为选择性干预提供了靶点。然而，在将这些发现应用于FSE患儿的治疗之前，还需要额外的关键信息。目前尚不清楚海马MRI变化是否发生得足够早，足以预测认知缺陷，从而对潜在的干预有用，或者观察到的细胞和认知障碍是FSE还是随后的癫痫发生的结果。确定炎症细胞因子白细胞介素(IL)-12的海马水平是否能区分癫痫大鼠和非癫痫大鼠，以及这种细胞因子是否与EFS引起的认知缺陷有关，是必要的。在本研究中，我们将评估一组经历FSE的大鼠的认知缺陷是否可以通过癫痫发作后早期可见的选择性MRI变化来预测，以及FSE后的认知和定位细胞缺陷是否在癫痫发生过程和自发性癫痫发作之前出现，并独立于此，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能区分脑电刺激后认知缺陷大鼠与海马依赖记忆完整大鼠，我们将比较脑电刺激后细胞因子变化和未变化大鼠。本研究的结果将为发热性癫痫发作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.