In utero ethanol exposure & development of GABAergic cortical interneurons

描述（由申请人提供）：妊娠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）。在脑中，FAS的特征是大体形态学的缺陷（例如，小头畸形、脑积水、脑穿通症、无脑积水）。产前慢性乙醇暴露损害未成熟大脑中的GABA能系统，从而影响抑制性调节，导致癫痫发作易感性增加和FAS相关感觉信息处理缺陷。在这个建议中，我们问是否长期乙醇消费（1-6%乙醇）在怀孕期间导致异常发育的GABA能系统的后代。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处置通过影响原始GABA能中间神经元迁移到其在新皮质内的通常层状位置而在皮质发生的早期表现出来。在啮齿类动物中，这些GABA能中间神经元主要从内侧神经节隆起（MGE）的皮质外产生，并切向迁移到发育中的新皮质。在具体目标1中，我们将定量评估MGE衍生细胞的切向迁移的模式和动力学，具体假设是切向迁移的破坏取决于子宫内乙醇损伤的剂量和时间。具体目标2将在异型和异时端脑切片共培养物中采用实时视频显微镜检查，以检验细胞内在和外在机制均有助于改变子宫内乙醇的切线迁移模式的特定假设。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检验子宫内乙醇暴露与GABA能系统相互作用对MGE衍生细胞的切向迁移产生影响的假设。总的来说，该项目将首次确定妊娠早期乙醇消耗对新皮质中特定和重要细胞群体的胚胎发育的影响，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质神经元回路的破坏如何成为FAS中观察到的许多行为异常的基础奠定基础。

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.