GABA-inflammation interplay in infantile spasms

项目总结 婴儿痉挛是在一系列婴儿癫痫脑病中出现的癫痫发作。 预后不良。它们是特定于年龄的，具有不同的机制和药物敏感性 癫痫发作。它们有多种病因，其中炎症过程也有牵连。一个 大脑早期发育的重要特征是存在去极化的GABAA受体信号， 正常发育所需，该受体逐渐转变为正常的超极化GABAA受体 信号出现在更成熟的年龄段。使用婴儿痉挛的大鼠和小鼠模型，我们发现了证据 去极化GABAA受体信号在局灶性皮质炎症环境中的存在，可能 年龄相关的易患炎症性痉挛的基础，并可能倾向于更严重的 表型。在这里，我们研究了去极化的GABAA受体信号和 导致痉挛的年龄特异性表达的炎症，并容易导致更严重的表型。我们 他们还将调查这种GABA-炎症和相互作用是否会影响成年后的癫痫发作。 我们将使用立体定向手术、视频脑电监测、组织学、基因和蛋白质的组合 表达研究，体外电生理学，药物给药来确定分子和 涉及的电生理机制和寻找新的婴幼儿治疗候选靶点 痉挛。我们的研究有望为开发新的治疗方法提供新的候选目标 婴儿痉挛和随后的癫痫。

PROJECT SUMMARY Infantile spasms are epileptic seizures that appear within a spectrum of infantile epileptic encephalopathies with poor prognosis. They are age-specific and have different mechanisms and pharmacosensitivity from other seizures. They have multiple etiologies, among which inflammatory processes have been implicated. An important feature of early brain development is the presence of depolarizing GABAA receptor signaling, needed for normal development, which gradually shifts to the normal hyperpolarizing GABAA receptor signaling seen in more mature ages. Using rat and mouse models of infantile spasms, we have found evidence that the presence of depolarizing GABAA receptor signaling in the setting of focal cortical inflammation, may underlie the age-specific susceptibility to inflammation-induced spasms and may predispose to a more severe phenotype. Here we investigate the interactions between depolarizing GABAA receptor signaling and inflammation that lead to age-specific expression of spasms and predispose to a more severe phenotype. We  will also investigate whether this GABA-­‐‑inflammation interaction affects subsequent epilepsy in adulthood. We will use a combination of stereotactic surgeries, video-EEG monitoring, histology, gene and protein expression studies, in vitro electrophysiology, drug administrations to determine the molecular and electrophysiological mechanisms involved and identify new candidate targets for novel treatments for infantile spasms. Our studies are expected to deliver new candidate targets for the development of new therapeutics for infantile spasms and subsequent epilepsies.