In utero ethanol exposure & development of GABAergic cortical interneurons

子宫内乙醇暴露

• 批准号: 7222441
• 负责人: Verginia Carmella Cuzon Carlson
• 金额: $ 4.2万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222441
• 关键词: GABA receptor; alcoholic beverage consumption; cell migration; electrophysiology; embryo /fetus toxicology; fetal alcohol syndrome; gamma aminobutyrate; genetically modified animals; green fluorescent proteins; immunocytochemistry; interneurons; laboratory mouse; mammalian embryology; mixed tissue /cell culture; neocortex; neurochemistry; neurogenesis; polymerase chain reaction; predoctoral investigator; video microscopy

DESCRIPTION (provided by applicant): Consumption of ethanol during pregnancy can be detrimental to the offspring, the most severe detriment being the developmental defects collectively referred to as fetal alcohol syndrome (FAS). In brain, FAS is hallmarked by defects in gross morphology (e.g., microcephaly, hydrocephaly, porencephaly, hydroanencephaly) that have been attributed to insult during corticogenesis. Prenatal chronic ethanol exposure compromises the GABAergic system in the immature brain and, thus, inhibitory regulation, contributing to increased susceptibility to seizures and deficits in sensory information processing associated with FAS. In this proposal, we ask whether chronic ethanol consumption (1-6% EtOH) during pregnancy leads to abnormal development of the GABAergic system in the offspring. The overriding hypothesis is that the abnormal disposition of the postnatal and mature cortex seen in FAS manifests itself early on in corticogenesis by affecting the migration of primordial GABAergic interneurons to their usual laminar positions within the neocortex. In rodent, these GABAergic interneurons arise extracortically primarily from the medial ganglionic eminence (MGE) and migrate tangentially into the developing neocortex. In Specific Aim 1, we will quantitatively assess the patterns and kinetics of the tangential migration of MGE-derived cells with the specific hypothesis that the disruption of tangential migration is dependent on the dose and time of ethanol insult in utero. Specific Aim 2 will employ real-time videomicroscopy in heterotypic and heterochronic telencephalic slice cocultures to test the specific hypothesis that both cell intrinsic and extrinsic mechanisms contribute to alter the pattern of tangentil migration with in utero ethanol. Specific Aim 3 will incorporate electrophysiological, gene profiling, and immunohistochemical approaches to test the hypothesis that in utero ethanol exposure interacts with the GABAergic system to exert its effect on tangential migration of MGE-derived cells. Overall, this project will for the first time define the effect of ethanol consumption during early stages of pregnancy on the embryonic development of a specific and important population of cells in the neocortex, notably the GABAergic cortical interneurons. In the long run, the proposed studies will lay the groundwork for assessing how disruptions of the cortical neuronal circuitry underlie many of the behavioral abnormalities seen in FAS.

描述（由申请人提供）：怀孕期间摄入乙醇可能对后代有害，最严重的损害是发育缺陷，统称为胎儿酒精综合征（FAS）。在脑部，FAS以大体形态学缺陷为特征（例如，小头畸形、脑积水、颅孔畸形、无脑积水），这些缺陷可归因于皮质发生过程中的损伤。产前慢性乙醇暴露会损害未成熟大脑中的gaba能系统，从而抑制调节，从而增加癫痫发作的易感性和与FAS相关的感觉信息处理缺陷。在本研究中，我们研究了怀孕期间长期摄入乙醇（1-6%乙醇）是否会导致后代gaba能系统的异常发育。最重要的假设是，在FAS中看到的出生后和成熟皮层的异常配置，通过影响原始gaba能中间神经元向新皮层中通常的层状位置的迁移，在皮质发生的早期就表现出来。在啮齿类动物中，这些gaba能中间神经元主要来自内侧神经节隆起（MGE），并向发育中的新皮层切向迁移。在Specific Aim 1中，我们将定量评估mge衍生细胞切向迁移的模式和动力学，并假设切向迁移的破坏取决于子宫内乙醇损伤的剂量和时间。特异性目标2将在异型和异慢性端脑片共培养中使用实时视频显微镜来测试细胞内在和外在机制有助于改变子宫内乙醇切向迁移模式的特定假设。特异性目的3将结合电生理学、基因谱分析和免疫组织化学方法来检验子宫内乙醇暴露与gaba能系统相互作用以发挥其对mge来源细胞切向迁移的影响的假设。总的来说，该项目将首次确定妊娠早期乙醇消耗对新皮层中特定和重要细胞群的胚胎发育的影响，特别是gaba能皮质中间神经元。从长远来看，拟议的研究将为评估皮层神经元回路的破坏如何成为FAS中许多行为异常的基础奠定基础。