CNS Development, GABAARS and Vulnerability to Ethanol

描述（由申请人提供）：在子宫内乙醇中毒后患有认知缺陷的儿童严重残疾，并在我们复杂的世界中努力取得成功。不幸的是，没有治疗方法可以预防或逆转这种损伤。我们的长期目标是合理地确定/测试可以保护发育中的神经回路不受乙醇损伤并保护认知功能的疗法。我们已经确定了乙醇扭曲新形成的突触时引起的GABA信号缺陷。由此产生的GABA张力的变化可能会扭曲认知神经回路中的信息处理，导致学习和记忆缺陷。即使酒精诱导的神经元丢失没有发生，也可能存在突触缺陷。在相当于人类第三孕期大脑发育的一段时间内，大鼠幼崽的暴食样中毒扭曲了大脑切片中内侧隔/斜角带神经元中GABA微型突触后电流的成熟。这种作用似乎在原代隔培养物中忠实地建模，令人惊讶的是，在培养物中，它在很大程度上被finalide阻止，finalide是一种阻止51-还原型神经类固醇形成的药物。如果GABA能突触功能障碍永久性地使抑制性输入偏向内侧隔/斜角带神经元，那么对认知性能至关重要的神经回路活动可能会受到损害。事实上，在空间学习和记忆任务的表现受损，无论是在儿童遭受胎儿酒精暴露和大鼠出生后早期中毒，这表明隔-海马电路可能是功能失调。在这里，我们测试的假设，第三个三个月相当于乙醇中毒扭曲的成熟GABA突触在内侧隔/斜角带和破坏相关的认知功能。还将使用已建立的体内啮齿动物酒精暴露过量模型、全细胞电生理学、受体药理学和行为评估来研究干预措施（如非那肽）是否可以闭塞乙醇诱导的缺陷。如果成功的话，这项工作可以提供一个模型来测试旨在预防或限制认知损伤的治疗方法。公共卫生相关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，并在我们复杂的世界中努力取得成功。不幸的是，没有治疗方法可以预防或逆转这种损伤。该项目的长期目标是合理确定和测试可以保护发育中的大脑免受乙醇损伤并保护有胎儿酒精谱系障碍风险的儿童的认知功能的疗法。

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.