CNS DEVELOPMENT, GABAARS AND VUNERABILITY TO ETHANOL

患有胎儿酒精综合征(FAS)的儿童患有精神缺陷 让他们终身残废。了解乙醇如何发挥其作用 细胞和分子水平的神经致畸作用可能提供 对改善中枢神经系统功能的干预设计的见解 这些人的结果。在这方面，现在很明显， GABA/AR主要是“兴奋性/神经营养”转导系统。 发育中的大脑，并承担起更广为人知的经典抑制作用 随着大脑的成熟。早期的GABA/AR使未成熟神经元去极化， 激活电压依赖性钙离子内流，刺激神经再生， 神经元的分化、迁移和突触形成。 目前，人们对乙醇对功能的影响知之甚少 或在未成熟的中枢神经系统表达“兴奋性”GABA/ARs。如果乙醇 扭曲了GABA/AR活性的正常发育模式，这 可能会导致Fas的神经功能缺陷。我们最近做了 发现大鼠内侧脑区GABA/ARs的出生后进化延迟 中度“狂欢”后一周的隔/斜角带(MS/DB)神经元 如“出生后酒精暴露。基本的GABA/AR功能在4-5岁时恢复 几周的生命，但锌/2+抑制的微妙更持久的变化 留下来。MS/DB患者出生后早期GABA/AR功能受损 可能会扭曲适当的突触形成并有助于注意力 自闭症患者特有的缺陷。该项目将使用 已建立的Fas啮齿动物体内模型，体外原代神经元 培养系统、免疫细胞化学、体视学和体外 单个神经元和脑片的电生理记录 产前酒精暴露对MS/DB功能的影响 发展。这些研究将检验这样的假设：“围产期 乙醇暴露抑制兴奋性GABA/ARs，后者干扰 神经元发育的正常模式。

Children with fetal alcohol syndrome (FAS), suffer mental deficits that handicap them for life. Understanding how ethanol exerts its neuroteratogenic action at a cellular and molecular level may offer insights into the design of interventions to improve CNS functional outcomes for these individuals. In this regard, it is now clear that GABA/ARs are predominantly "excitatory/neurotrophic" transducers in developing brain and take on the better known, classical inhibitory role as the brain matures. Early GABA/ARs depolarize immature neurons, activating voltage-dependent Ca/2+ entry and stimulating neurogenesis, neuronal differentiation, migration as well as synaptogenesis. Currently, little is known about the impact of ethanol on the function or expression of "excitatory" GABA/ARs in the immature CNS. If ethanol distorts the normal developmental pattern of GABA/AR activity, this could contribute to neurological deficits in FAS. We have recently identified a delay in the postnatal evolution of GABA/ARs in rat medial septal/diagonal band (MS/DB) neurons one week after moderate "binge- like" postnatal ethanol exposure. Basic GABA/AR function recovers bu 4-5 weeks of life, but subtle longer-lasting changes in Zn/2+ inhibition remain. Impairment of early postnatal GABA/AR function in the MS/DB could distort appropriate synapse formation and contribute to attention deficits characteristic of individuals with FAS. This project will use well-established in vivo rodent models of FAS, in vitro primary neuronal culture systems, immunocytochemistry, stereology and in vitro electrophysiological recordings in individual neurons and brain slices to determine the impact of prenatal ethanol exposure on MS/DB functional development. These studies will test the hypothesis that: "Perinatal ethanol exposure inhibits excitatory GABA/ARs which interferes with normal patterns of neuronal development."