CNS Development, GABAARS and Vulnerability to Ethanol

描述(申请人提供)：在子宫内酒精中毒后患有认知缺陷的儿童严重残疾，并在我们这个复杂的世界中挣扎着取得成功。可悲的是，目前还没有预防或逆转这种伤害的治疗方法。我们的长期目标是合理地识别/测试可以保护发育中的神经回路免受酒精损伤并保护认知功能的治疗方法。我们已经确定了酒精扭曲新形成的突触时造成的GABA信号的缺陷。由此导致的GABA音调的变化可能会扭曲认知神经回路中的信息处理，导致学习和记忆障碍。即使在酒精诱导的神经元丢失没有发生的情况下，突触缺陷也可能存在。在相当于人类晚期大脑发育的一段时间内，幼鼠的暴饮式中毒扭曲了脑片内侧隔/斜角带神经元中GABA微小突触后电流的成熟。这种作用似乎在原代间隔培养中得到了忠实的模拟，令人惊讶的是，在培养中，它在很大程度上被非那雄胺所阻止，非那雄胺是一种阻止51-还原神经类固醇形成的药物。如果GABA能突触功能障碍永久性地扭曲内侧隔/斜角带神经元的抑制性输入，那么对认知能力至关重要的神经回路活动可能会受到影响。事实上，无论是胎儿酒精暴露的儿童，还是出生后早期中毒的大鼠，在空间学习和记忆任务中的表现都受到了损害，这表明隔区-海马区回路可能功能障碍。在这里，我们测试了一种假设，即妊娠晚期相当于酒精中毒扭曲了内侧隔/斜角带中GABA突触的成熟，并扰乱了相关的认知功能。像非那雄胺这样的干预措施是否可以阻断乙醇诱导的缺陷也将使用建立的狂饮酒精暴露的体内啮齿动物模型、全细胞电生理学、受体药理学和行为评估来研究。如果成功，这项工作可能会为测试旨在预防或限制认知损伤的治疗方法提供一个模型。公共卫生关注性怀孕期间因酒精中毒而出现认知缺陷的儿童可能会严重残疾，并在我们这个复杂的世界中挣扎着取得成功。可悲的是，目前还没有预防或逆转这种伤害的治疗方法。该项目的长期目标是合理地确定和测试可以保护发育中的大脑免受酒精损伤的治疗方法，并保护有胎儿酒精谱系障碍风险的儿童的认知功能。

DESCRIPTION (provided by applicant): Children who suffer cognitive deficits after in utero ethanol intoxication are severely handicapped and struggle to succeed in our complex world. Sadly, there are no treatments to prevent or reverse this injury. Our long- term goal is to rationally identify / test therapies that could protect developing neurocircuits from ethanol injury and preserve cognitive functioning. We have identified a defect in GABA signaling caused when ethanol distorts newly forming synapses. Resulting changes in GABA tone could skew information processing in cognitive neurocircuits causing learning and memory deficits. Synaptic defects could be present even when alcohol-induced neuronal loss does not occur. During a period equivalent to human 3rd trimester brain development, binge-like intoxication in rat pups distorts maturation of GABA miniature postsynaptic currents in medial septum / diagonal band neurons in brain slices. This action seems to be faithfully modeled in primary septal cultures and surprisingly, in cultures, it is largely prevented by finasteride, a drug that blocks formation of 51-reduced neurosteroids. If GABAergic synaptic dysfunction permanently skews inhibitory input to medial septum / diagonal band neurons, then neurocircuit activity essential for cognitive performance could be compromised. In fact, performance in spatial learning and memory tasks is impaired both in children suffering from fetal alcohol exposure and in rats after early postnatal intoxication, suggesting that septal-hippocampal circuits could be dysfunctional. Here we test the hypothesis that 3rd trimester equivalent ethanol intoxication distorts maturation of GABA synapses in the medial septum / diagonal band and disrupts associated cognitive functioning. Whether an intervention such as finasteride can occlude ethanol-induced deficits also will be studied using an established in vivo rodent model of binge ethanol exposure, whole cell electrophysiology, receptor pharmacology and behavioral assessment. If successful, this work could provide a model for testing treatments aimed at offering hope for preventing or limiting cognitive injury. PUBLIC HEALTH RELEVANCE Children who suffer cognitive deficits from ethanol intoxication during pregnancy can be severely handicapped and struggle to succeed in our complex world. Sadly, there are no treatments to prevent or reverse this injury. The long-term goal of this project is to rationally identify and test therapies that could protect the developing brain from ethanol injury and preserve cognitive functioning in children at risk for fetal alcohol spectrum disorders.