GABA-inflammation interplay in infantile spasms

 描述（由申请人提供）：婴儿痉挛是一种癫痫发作，出现在一系列婴儿癫痫性脑病中，预后不良。它们具有年龄特异性，并且具有与其他癫痫发作不同的机制和药物敏感性。他们有多种病因，其中炎症过程已牵连。早期脑发育的一个重要特征是存在正常发育所需的去极化GABAA受体信号传导，其逐渐转变为在更成熟年龄中观察到的正常超极化GABAA受体信号传导。使用婴儿痉挛症的大鼠和小鼠模型，我们已经发现证据表明，在局灶性皮质炎症的背景下存在去极化GABAA受体信号传导，可能是年龄特异性对炎症诱导的痉挛的易感性的基础，并且可能倾向于更严重的表型。在这里，我们研究去极化GABAA受体信号传导和炎症之间的相互作用，导致痉挛的年龄特异性表达，并倾向于更严重的表型。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，基因和蛋白质表达研究，体外电生理学和药物管理相结合，以确定所涉及的分子和电生理机制，并确定新的候选目标婴儿痉挛症的新治疗方法。我们的研究有望为婴儿痉挛症和继发性癫痫的新疗法的开发提供新的候选靶点。

 DESCRIPTION (provided by applicant): 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, and 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.