Epileptogenic effects of periventricular nodular heterotopia

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。这些异常结构有时统称为皮质发育不良，通常反映了发育性脑缺陷。我们建议研究一种称为脑室周围结节性异位（PNH）的皮质发育不良的动物模型。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层的适当位置。大多数患有此病的人都患有癫痫，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/或癫痫发作的起始部位，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。我们目前的目标是深入了解pnh相关癫痫发作是如何以及在何处发生的。我们拟建立孕鼠经甲氧基甲醇（MAM）处理后的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和PNH结构和周围（明显正常的）皮层的功能完整性。这些程序将应用于完整的动物，急性脑切片和器官型培养，以评估包含PNH样病变的皮层的一般电路功能，以及PNH内外单个神经元的特性。在器官型切片制备中，我们将检查去除PNH的后果（例如，作为神经外科医生可能会治疗人类大脑的疾病），以评估这种操作作为大脑发育功能的功效。健康相关性：脑结构发育异常（如脑室周围结节性异位）的发生通常与癫痫等癫痫性疾病和其他认知缺陷有关。因为我们对这种结构异常是如何引起癫痫的了解相对较少，所以我们有效治疗癫痫的能力有限。本建议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（在大脑发育的不同时期）作为治疗手段的有效性。

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.