In utero ethanol exposure & development of GABAergic cortical interneurons

在怀孕期间摄入乙醇可能对后代有害，这是最严重的伤害。 这些发育缺陷统称为胎儿酒精综合征（FAS）。在大脑中，FAS是 其特征在于总体形态上的缺陷（例如，小头畸形，脑积水，脑穿孔， 积水性无脑畸形）。产前慢性乙醇 暴露损害未成熟脑中的GABA能系统，因此，抑制性调节， 有助于增加癫痫发作的易感性和与癫痫发作相关的感觉信息处理的缺陷， 关于FAS 在这项提案中，我们询问怀孕期间长期饮用乙醇（1-6% EtOH）是否会导致 后代中GABA能系统的异常发育。最重要的假设是， 在FAS中观察到的出生后和成熟皮质的异常分布在 通过影响原始GABA能中间神经元向其通常板层的迁移， 在新皮层中的位置。在啮齿类动物中，这些GABA能中间神经元主要从皮质外产生， 内侧神经节隆起（MGE），并切向迁移到发育中的新皮质。在特定 目的1，我们将定量评估MGE衍生的切向迁移的模式和动力学， 细胞的特定假设，即切向迁移的破坏取决于剂量， 子宫内乙醇损伤时间。具体目标2将采用实时视频显微镜在异型和 异时端脑切片共培养以测试细胞内在和 外源性机制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，基因谱分析和免疫组织化学方法来测试 假设子宫内乙醇暴露与GABA能系统相互作用， MGE衍生细胞的切向迁移。 总的来说，该项目将首次确定乙醇消费在早期阶段的影响， 怀孕对胚胎发育的一个特定的和重要的细胞群体的新皮层， 特别是GABA能皮质中间神经元。长远而言，拟议的研究将为 用于评估皮层神经元回路的中断是如何导致许多行为异常的 在FAS中看到

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.