Epileptogenic effects of periventricular nodular heterotopia

脑室周围结节性异位的致癫痫作用

• 批准号: 7563314
• 负责人: PHILIP A SCHWARTZKROIN
• 金额: $ 32.11万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563314
• 关键词: Acute; Animal Model; Animals; Ara-C; Brain; Cells; Clinical Research; Cognitive deficits; Cortical Dysplasia; Defect; Development; Epilepsy; Excision; Eye; Gene Mutation; Goals; Human; Individual; Lesion; Location; Modeling; Neurons; Neurosurgeon; Newborn Infant; Perinatal; Pharmaceutical Preparations; Preparation; Procedures; Property; Rattus; Seizures; Site; Slice; Structure; Suggestion; Techniques; Time; Tissues; Traumatic Brain Injury; base; experience; insight; methylazoxymethanol; migration; pregnant

DESCRIPTION (provided by applicant): Epilepsies are often associated with abnormalities in brain structure. These abnormalities take many different forms, and can be a consequence of gene mutations, perinatal insults, or brain trauma. The aberrant structures collectively sometimes referred to as cortical dysplasias frequently reflect developmental brain defects. We propose to study an animal model of one type of cortical dysplasia, called periventricular nodular heterotopia (PNH). This condition is most frequently a result of a gene mutation that interferes with normal migration of newborn cells into their proper location in the cortex. Most people with this condition suffer from a seizure disorder, often unresponsive to medication. Some clinical studies have suggested these heterotopias serve as initiation sites of epileptic discharge and/or seizures, but these studies have been unable to establish an unequivocal cause-effect relationship between structural and functional abnormalities. Our goal in the current proposal is to gain insight into how and where PNH-associated seizures develop. We plan to study a rat model of PNH induced by treating the pregnant dam with methylazoxymethanol (MAM). We will use electrical recording and neuropathological techniques to assess tissue excitability and the functional integrity of the PNH structure and surrounding (and apparently normal) cortex. These procedures will be applied in the intact animal, in acute brain slices, and in organotypic cultures, in order to evaluate both the general circuitry function in cortex containing a PNH-like lesion, and also the properties of individual neurons both within and outside the PNH. In the organotypic slice preparation, we will examine the consequences of removing the PNH (e.g., as a neurosurgeon might do to treat the condition in human brain), in order to assess the efficacy of such manipulations as a function of brain development. PUBLCI HEALTH RELEVANCE: The occurrence of developmentally-based abnormalities in brain structure (e.g., periventricular nodular heterotopia) is commonly associated with seizure disorders i.e., epilepsy and other cognitive deficits. Because we understand relatively little about how this type of structural abnormality gives rise to epilepsy, our ability to treat the epilepsy effectively is limited. The aim of this proposal is to gain an understanding of the causal relationship between the structural aspects of these disorders and seizures, and to assess the efficacy of surgical removal (at different times during brain development) as a means of therapy.

描述（由申请人提供）：癫痫通常与大脑结构异常有关。这些异常有多种不同的形式，可能是基因突变、围产期损伤或脑外伤的结果。有时统称为皮质发育不良的异常结构经常反映大脑发育缺陷。我们建议研究一种皮质发育不良的动物模型，称为脑室周围结节性异位（PNH）。这种情况最常见的原因是基因突变干扰了新生细胞正常迁移到皮质中的正确位置。大多数患有这种疾病的人患有癫痫症，通常对药物没有反应。一些临床研究表明这些异位是癫痫放电和/或癫痫发作的起始位点，但这些研究无法在结构和功能异常之间建立明确的因果关系。我们当前提案的目标是深入了解 PNH 相关癫痫发作的方式和地点。我们计划研究用甲基偶氮甲醇 (MAM) 处理怀孕母鼠诱导的 PNH 大鼠模型。我们将使用电记录和神经病理学技术来评估组织兴奋性以及 PNH 结构和周围（显然正常）皮质的功能完整性。这些程序将应用于完整动物、急性脑切片和器官培养物中，以评估包含 PNH 样病变的皮层中的一般电路功能，以及 PNH 内外单个神经元的特性。在器官切片制备中，我们将检查去除 PNH 的后果（例如，神经外科医生可能会治疗人脑疾病），以评估此类操作作为大脑发育功能的功效。公共健康相关性：基于发育的大脑结构异常（例如，脑室周围结节性异位）的发生通常与癫痫症（即癫痫和其他认知缺陷）相关。由于我们对这种类型的结构异常如何引起癫痫了解相对较少，因此我们有效治疗癫痫的能力有限。该提案的目的是了解这些疾病的结构方面与癫痫发作之间的因果关系，并评估手术切除（在大脑发育过程中的不同时间）作为治疗手段的功效。