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， 让他们终身残疾了解乙醇如何发挥其 细胞和分子水平的神经致畸作用可能提供 对改善CNS功能的干预措施设计的见解 这些人的结果。在这方面，现在很清楚， GABA/AR主要是“兴奋性/神经营养性”转换器， 发展中的大脑，并采取更好地了解，经典的抑制作用 随着大脑的成熟早期GABA/AR使未成熟神经元退化， 激活电压依赖性Ca/2+内流并刺激神经发生， 神经元分化、迁移以及突触发生。 目前，关于乙醇对功能的影响知之甚少。 或未成熟CNS中“兴奋性”GABA/AR的表达。如果乙醇 扭曲了GABA/AR活性的正常发育模式， 可能导致FAS中的神经功能缺损。我们最近 确定了大鼠中GABA/AR的出生后演变延迟， 隔/斜角带（MS/DB）神经元中度“狂欢”后一周， 比如”产后酒精暴露“GABA/AR基本功能4-5年恢复 但Zn/2+抑制的微妙持久变化 保持。MS/DB出生后早期GABA/AR功能受损 可能会扭曲适当的突触形成， FAS患者的特征性缺陷。This project will use FAS的良好建立的体内啮齿动物模型，体外原代神经元 培养系统、免疫细胞化学、体视学和体外 单个神经元和脑切片的电生理记录 确定产前乙醇暴露对MS/DB功能的影响 发展这些研究将检验以下假设：“围产期 乙醇暴露抑制兴奋性GABA/AR，其干扰 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."