CNS Development, GABAARS and Vulnerability to Ethanol

描述（由申请人提供）：在子宫内乙醇中毒后出现认知缺陷的儿童严重残疾，在我们这个复杂的世界中很难取得成功。遗憾的是，没有任何治疗方法可以预防或逆转这种伤害。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免受乙醇损伤并保持认知功能的治疗方法。我们已经确定了当乙醇扭曲新形成的突触时，GABA信号的缺陷。GABA音调的变化可能会扭曲认知神经回路中的信息处理，从而导致学习和记忆缺陷。即使酒精引起的神经元丧失没有发生，突触缺陷也可能出现。在相当于人类大脑发育的第三孕期，大鼠幼崽暴饮暴食样中毒会扭曲脑切片中中隔/对角带神经元中GABA微型突触后电流的成熟。这种作用似乎在初级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，非那雄胺是一种阻断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了对内侧隔/对角带神经元的抑制性输入，那么对认知表现至关重要的神经回路活动可能会受到损害。事实上，无论是胎儿酒精中毒的儿童，还是出生后早期中毒的大鼠，其空间学习和记忆任务的表现都受到了损害，这表明间隔-海马回路可能功能失调。在这里，我们验证了一个假设，即妊娠晚期等效乙醇中毒会扭曲内侧隔/对角线带GABA突触的成熟并破坏相关的认知功能。非那雄胺等干预措施是否可以阻断乙醇诱导的功能缺陷也将通过一个已建立的啮齿动物体内酒精暴露模型、全细胞电生理学、受体药理学和行为评估来研究。如果成功，这项工作可以为测试治疗提供一个模型，旨在为预防或限制认知损伤提供希望。在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，在我们这个复杂的世界中很难取得成功。遗憾的是，没有任何治疗方法可以预防或逆转这种伤害。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乙醇损伤的治疗方法，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.