In utero ethanol exposure & development of GABAergic cortical interneurons

描述(由申请人提供)：怀孕期间饮用酒精可能对后代有害，最严重的损害是统称为胎儿酒精综合症(FAS)的发育缺陷。在大脑中，Fas的特征是大体形态上的缺陷(如小头畸形、脑积水、多孔性脑畸形、积水性无脑)，这些缺陷被归因于皮质生成过程中的侮辱。产前长期酒精暴露会损害未成熟大脑中的GABA能系统，从而抑制调节，导致癫痫发作的易感性增加，并导致与Fas相关的感觉信息处理缺陷。在这项建议中，我们询问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，Fas中所见的出生后和成熟皮质的异常处置在皮质发生的早期就表现出来，通过影响原始的GABA能中间神经元迁移到它们在新皮质中的正常片层位置。在啮齿动物中，这些GABA能中间神经元主要来自内侧神经节隆起(MGE)，并切向迁移到发育中的新皮质。在特定的目标1中，我们将定量评估MGE来源的细胞的切向迁移的模式和动力学，具体假设是切向迁移的中断依赖于宫内乙醇的剂量和时间。特定目标2将在异型和异时端脑切片共培养中使用实时视频显微镜来测试特定的假设，即细胞内在和外部机制都有助于改变子宫内乙醇的切线迁移模式。具体目标3将结合电生理学、基因图谱和免疫组织化学方法来验证这样的假设，即子宫内乙醇暴露与GABA能系统相互作用，对MGE来源的细胞的切向迁移发挥作用。总体而言，该项目将首次确定怀孕早期酒精摄入对新皮质中一组特定和重要的细胞，特别是GABA能皮质中间神经元的胚胎发育的影响。从长远来看，拟议中的研究将为评估皮层神经元回路的中断如何导致Fas中的许多行为异常奠定基础。

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.