Limbic Excitability After Febrile Seizures.

热性(发烧引起)癫痫是儿童癫痫最常见的形式，影响3%-5%的儿童癫痫 美国和世界各地的婴幼儿。尽管发烧的发病率很高，但 癫痫，发热性癫痫在发育中的大脑是否以及如何改变神经元回路是不好的 明白了。在上一个奖项中，我们使用了一种适当年龄的发热性癫痫鼠模型， 确定在幼年大鼠的实验性热性惊厥导致持续增加的数量 大麻素受体1型(CB1-)受体，并增强CB1介导的活性- 依赖的，逆行抑制神经递质GABA在海马区的释放。这里 我们建议检验这样的假设：1.热性惊厥选择性地改变内源性、突触和电信号。 表达CB1篮子细胞的偶联特性，而不改变其他类型的互变异构性 2.热性惊厥持续增加CB1受体介导的紧张性抑制 3.实验性发热过程中CB1受体的激活 婴儿期癫痫发作是导致边缘网络兴奋性发生长期变化的关键一步。 这些假说将使用电生理学方法和 免疫细胞化学技术，辅以大规模的，解剖学和生物物理学的现实， 计算网络建模方法，允许系统测试以下各项的相对重要性 不同的，实验确定的，癫痫发作引起的过度兴奋的改变。两种类型的控件 将采用：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， 使用药理药剂阻止癫痫发作。我们的初步数据表明，从长期来看 哺乳动物中最丰富的G蛋白偶联受体CB1受体的变化 大脑在边缘兴奋性增强的发展和维持中起着关键的机械作用 在实验性发热性癫痫发作后。这项提案中的实验是专门针对主要 婴儿期热性癫痫发作后兴奋性高的细胞-突触机制 预计拟议的实验可能为抗癫痫提供新的未来治疗途径 儿童的药物治疗。

Febrile (fever-induced) seizures are the most common forms of childhood seizures, affecting 3%-5% of infants and young children in the United States and worldwide. In spite of the high incidence of fever-induced seizures, whether and how febrile seizures in the developing brain alter neuronal circuits is not well understood. Under the previous award, using an appropriate-aged rodent model of febrile seizures, we determined that experimental febrile seizures in infant rats resulted in a persistent increase in the number of cannabinoid receptor type 1- (CB1-) receptors, and an enhancement of the CB1-mediated, activity- dependent, retrograde suppression of the release of the neurotransmitter GABA in the hippocampus. Here we propose to test the hypotheses that 1. febrile seizures selectively alter the intrinsic, synaptic and electrical coupling properties of the CB1-expressing basket cells, without modifying other types of perisomatically projecting interneurons; 2. febrile seizures persistently increase the CB1 receptor-mediated tonic inhibition of GABA-release from basket cell terminals; and that 3. CB1 receptor activation during the experimental febrile seizures in infancy is a key step in causing long-lasting changes in limbic network excitability. These hypotheses will be tested using a combination of electrophysiological methods and immunocytochemical techniques, complemented by large-scale, anatomically and biophysically realistic, computational network modeling approaches that allow the systematic testing of the relative importance of the various, experimentally determined, seizure-induced alterations in hyperexcitability. Two types of controls will be employed: 1) age-matched, normothermic sham controls, and 2) age-matched, hyperthermic controls, in which the seizures are blocked using pharmacological agents. Our Preliminary data indicate that long-term alterations in CB1 receptors, which are the most abundant G-protein-coupled receptors in the mammalian brain, play crucial mechanistic roles in the development and maintenance of increased limbic excitability after experimental febrile seizures. The experiments in this proposal are designed to specifically target major cellular-synaptic mechanisms underlying hyperexcitabilityfollowing febrile seizures in infancy, and it is anticipated that the proposed experiments may provide novel future therapeutic avenues for anti-epileptic drug therapies in children.