GABA-inflammation interplay in infantile spasms

项目摘要 婴儿痉挛是癫痫发作，出现在一系列婴儿癫痫性脑病 预后不佳。它们具有年龄特异性，并且具有与其他药物不同的机制和药物敏感性。 癫痫发作他们有多种病因，其中炎症过程已牵连。一个 早期脑发育的重要特征是存在去极化GABAA受体信号传导， 正常发育所需，逐渐转移到正常的超极化GABAA受体 在更成熟的年龄看到的信号。使用婴儿痉挛症的大鼠和小鼠模型，我们发现了证据， 在局灶性皮质炎症的情况下，去极化GABAA受体信号的存在可能 是年龄特异性炎症诱发痉挛易感性的基础， 表型。在这里，我们研究了去极化GABAA受体信号传导和 炎症导致痉挛年龄特异性表达，并易于形成更严重的表型。我们 还将研究这种GABA-炎症相互作用是否会影响成年后的癫痫。 我们将使用立体定向手术，视频脑电图监测，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，以确定分子和 涉及的电生理机制，并确定新的候选目标，为新的治疗婴儿 痉挛我们的研究有望为开发新的治疗药物提供新的候选靶点， 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.