Limbic Excitability after Febrile Seizures

描述(由申请人提供)：发烧(由发烧引起)癫痫是 最常见的儿童癫痫发作形式，影响3%至5% 在美国和全世界，婴儿和幼儿的百分比。在……里面 尽管发烧引起的癫痫发病率极高，但是否和 发育期大脑中的发热性惊厥如何改变神经元回路 很好理解。事实上，癫痫最具争议的问题之一是 婴儿期惊厥与其以后发展的关系 颞叶癫痫。回顾性的临床研究表明，有大量的 部分顽固性颞叶癫痫患者有以下病史 婴儿时期发热性癫痫发作。然而，前瞻性研究未能发现 这个协会。近日，一种适龄啮齿动物模型 已引入热疗诱发癫痫，适用于研究 热性惊厥的发病机制和后遗症。在上一个奖项中，我们使用了 用这种实验性热性惊厥模型来确定实验性癫痫 幼年大鼠热性惊厥导致突触前持续性增加 在抑制中，但在特定突触后离子通道中同时发生变化 (H-通道)矛盾地将增强的抑制转化为 过度兴奋。在这里，我们建议检验这一假设 高温诱发癫痫导致持续性、超同步性发作 海马区主细胞的抑制性突触输入。具体的 AIMS将使用膜片钳电生理、免疫细胞化学进行测试 和计算建模技术。将使用两种类型的控制： 1)年龄匹配的常温假对照组，以及2)年龄匹配的高热对照组 对照组，用药物阻断癫痫发作。 初步数据表明，一种特定类型的中间神经元参与了 突触后细胞超同步抑制性输入的产生 在实验性发热性癫痫发作后。其他初步结果表明 大麻素-1受体的激活可以有效地调节 癫痫发作后向主细胞的超同步抑制输入，在 与最近关于大麻素-L受体表达的报道一致 在特定的神经元间轴突终末。从建议中获得的数据 实验将确定在相互作用中的长期变化 中间神经元和主细胞可以被调节，这将有助于识别 可作为抗癫痫药物治疗靶点的新机制 孩子们。

DESCRIPTION (provided by applicant): Febrile (fever-induced) seizures are the most common forms of childhood seizures, affecting three percent to five percent of infants and young children in the United States and worldwide. In spite of the extremely high incidence of fever-induced seizures, whether and how febrile seizures in the developing brain alter neuronal circuits is not well understood. Indeed, one of the most controversial issues in epilepsy is the relationship of convulsions in infancy to the subsequent development of temporal lobe epilepsy. Retrospective clinical studies indicated that a large fraction of patients with intractable temporal lobe epilepsy have a history of febrile seizures as infants. However, prospective studies have failed to find this association. Recently, an appropriate-aged rodent model of hyperthermia-induced seizures has been introduced, suitable for studying the mechanisms and sequelae of febrile seizures. Under the previous award, we used this model of experimental febrile seizures to determine that experimental febrile seizures in infant rats resulted in a persistent, presynaptic increase in inhibition, but concurrent changes in specific postsynaptic ion channels (h-channels) paradoxically converted the potentiated inhibition to hyperexcitability. Here we propose to test the hypothesis that hyperthermia-induced seizures result in persistent, hyper-synchronous inhibitory synaptic inputs to principal cells in the hippocampus. The specific aims will be tested using patch clamp electrophysiological, immunocytochemical and computational modeling techniques. Two types of controls will be employed: 1) age-matched, normothermic sham controls, and 2) age-matched, hyperthermic controls, in which the seizures were blocked using pharmacological agents. Preliminary data indicate that a specific type of interneuron is involved in the generation of hyper-synchronous inhibitory inputs to postsynaptic cells after experimental febrile seizures. Additional preliminary results suggest that activation of cannabinoid-1 receptors can potently modulate the hyper-synchronous inhibitory inputs to principal cells after the seizures, in agreement with recent reports showing the expression of cannabinoid-l receptors on specific interneuronal axon terminals. The data obtained from the proposed experiments will determine how long-term alterations in the interactions of interneurons and principal cells can be regulated, and will help to identify novel mechanisms that could be targeted for anti-epileptic drug therapies in children.