Epileptogenic effects of periventricular nodular heterotopia

脑室周围结节性异位的致癫痫作用

• 批准号: 7464129
• 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/7464129
• 关键词: ARHGEF5 gene; Acute; Age; Animal Model; Animals; Brain; CDKN1A gene; Cells; Chemical Agents; Clinical Research; Cognitive deficits; Condition; Control Animal; Cortical Dysplasia; Data Set; Defect; Development; Electric Stimulation; Electroencephalography; Epilepsy; Equilibrium; Excision; Exhibits; Exposure to; FOS gene; Gene Mutation; Goals; Human; In Situ Hybridization; Individual; Lesion; Location; Measures; Metabolic; Methods; Modeling; Neurons; Neurosurgeon; Newborn Infant; Pathway interactions; Patient currently pregnant; Pattern; Perinatal; Pharmaceutical Preparations; Preparation; Procedures; Property; Pyramidal Cells; Rattus; Seizures; Site; Slice; Staining method; Stains; Structure; Synapses; System; Techniques; Time; Tissues; Traumatic Brain Injury; base; cell type; immature animal; immunocytochemistry; insight; interest; kainate; methylazoxymethanol; migration; oncoprotein p21; periventricular heterotopia; response; sex

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）：癫痫通常与脑结构异常有关。这些异常有许多不同的形式，可能是基因突变、围产期损伤或脑外伤的结果。这些异常的结构有时统称为皮质发育不良，常常反映发育中的大脑缺陷。我们建议研究一种称为室周结节性异位（PNH）的皮质发育不良动物模型。这种情况通常是由于基因突变干扰了新生细胞正常迁移到大脑皮层的正确位置。大多数患有这种疾病的人患有癫痫发作，通常对药物无反应。一些临床研究表明，这些异位作为癫痫放电和/或癫痫发作的起始位点，但这些研究一直无法建立一个明确的因果关系之间的结构和功能异常。我们在当前提案中的目标是深入了解PNH相关癫痫发作是如何以及在何处发展的。我们计划研究大鼠PNH模型 通过用甲基偶氮氧基甲醇（MAM）处理妊娠母鼠诱导。我们将使用电记录和神经病理学技术来评估组织的兴奋性和功能完整性的PNH结构和周围（和显然正常）的皮质。这些程序将应用于完整的动物，在急性脑切片，并在器官型培养，以评估在皮质含有PNH样病变的一般电路功能，以及PNH内和外的单个神经元的属性。在器官型切片制备中，我们将检查去除PNH的后果（例如，就像神经外科医生治疗人脑中的病症一样），以便评估这种操作作为大脑发育的函数的功效。公共卫生相关性：大脑结构中发育异常的发生（例如，室周结节性异位）通常与癫痫发作有关即，癫痫和其他认知缺陷。由于我们对这种结构异常如何引起癫痫的了解相对较少，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和癫痫发作的结构方面之间的因果关系，并评估手术切除（在大脑发育期间的不同时间）作为治疗手段的有效性。