The role of brainstem in the generation of infantile spasms

描述（由申请人提供）：婴儿痉挛是一种年龄特异性癫痫综合征，表现为丛集性痉挛，神经认知发育受损，并常演变为顽固性癫痫。目前对婴儿痉挛的治疗并不总是有效的，而且经常伴有严重的副作用。正如最近在国家癫痫研究中心资助的治疗癫痫会议（2007年）上认识到的那样，迫切需要开发新的有效疗法来治疗这种综合征。在这个项目中，我们计划使用一种新的和唯一的大鼠症状性婴儿痉挛模型，研究该综合征的病理生理学，确定治疗效果的生物标志物，并在此基础上筛选新的治疗方法。在初步研究中，我们已经确定了多巴胺能黑质致密部神经元的生理和功能异常。我们的具体目的是确定这些是与痉挛表达或易感性相关的临界或间歇现象，并确定增强GABAA受体超极化效应的药物是否可以提高现有GABAA能抗癫痫药物在抑制与痉挛相关的体外异常以及治疗痉挛方面的疗效。为此，我们将结合使用多种技术，包括立体定向手术和药物微输注、行为监测、体内和体外电生理学、染色和共聚焦成像的组织学和免疫荧光方法，以及定量RT-PCR的基因表达分析。预计在本研究结束时，我们将知道所鉴定的体外异常是否为快速筛选婴儿痉挛新疗法的有效体外生物标志物。此外，一种改善目前使用的抗癫痫药物的潜在有益方法可能被证明对婴儿痉挛的治疗有益。摘要：婴儿痉挛是一种年龄特异性的、难以治疗的癫痫综合征，通常与神经发育障碍有关，特别是在先前存在大脑异常的婴儿中（症状性婴儿痉挛）。鉴于寻找新的有效治疗方法的紧迫性，我们计划研究一种新的症状性婴儿痉挛模型，以确定和验证新的体外治疗效果生物标志物，这将允许快速筛选新的候选治疗方法。我们期望这项研究的结果将为该病的病理生理学提供新的见解，为有效的治疗开辟新的途径。

DESCRIPTION (provided by applicant): Infantile spasms are an age-specific epileptic syndrome manifesting as clusters of spasms, impaired neurocognitive development, and often evolution to intractable epilepsy. The current treatment of infantile spasms is not always effective and is often associated with serious side effects. There is an urgent need to develop new effective therapies for this syndrome, as recognized recently in the NINDS-funded Curing Epilepsy meeting (2007). In this project, we plan to use a novel and only model of symptomatic infantile spasms in rats, to investigate the pathophysiology of this syndrome, identify biomarkers of therapeutic efficacy, upon which to screen new therapies. In preliminary studies, we have identified abnormalities in the physiology and function of the dopaminergic substantia nigra pars compacta neurons. Our specific aims are to determine whether these are ictal or interictal phenomena linked with the expression or predisposition to spasms and determine whether drugs that enhance the hyperpolarizing effects of GABAA receptors may increase the efficacy of existing GABAAergic antiepileptic drugs in suppressing the in vitro abnormalities associated with spasms as well as in treating spasms. To this end, we will use a combination of techniques, including stereotactic surgery and microinfusion of drugs, behavioral monitoring, in vivo and in vitro electrophysiology, histological and immunofluorescence methods of staining and confocal imaging, and gene expression analysis by quantitative RT-PCR. It is expected that at the conclusion of this study we will know whether the identified in vitro abnormalities are valid in vitro biomarkers for rapid screening of new therapies for infantile spasms. Furthermore, a potentially beneficial method of improving currently used antiepileptic drugs may be proven to-be beneficial in the treatment of infantile spasms. Lay Summary: Infantile spasms are an age-specific, difficult to treat, epileptic syndrome, often associated with neurodevelopmental impairments, especially in infants with pre-existing brain abnormalities (symptomatic infantile spasms). Given the urgency to identify new effective therapies, we plan to study a novel model of symptomatic infantile spasms, to identify and validate novel in vitro biomarkers of therapeutic efficacy, which will allow rapid screening of novel candidate therapies. We anticipate that the outcome of this study will provide new insights into the pathophysiology of the disease opening new avenues for effective treatments.