Abstract：
Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE.
摘要：
产前酒精暴露会对学习产生持续影响，记忆,和突触可塑性。我们小组先前的工作表明，在怀孕期间消耗适量酒精的大鼠大坝成年后代中，齿状回颗粒细胞上的兴奋性突触的长期增强（LTP）缺陷。目前,没有药物治疗药物批准这些缺陷。先前的工作确定，全身施用组胺能H3R反向激动剂ABT-239可逆转中度PAE后观察到的LTP缺陷。本研究检查了第二种H3R反向激动剂的作用，SAR-152954，关于温和PAE后的LTP赤字。我们证明，全身施用1mg/kg的SAR-152954可以逆转暴露于中度PAE的成年雄性大鼠的场兴奋性突触后电位（fEPSP）增强的缺陷。诱发反应的时频分析显示，在fEPSP期间，与PAE相关的功率降低，以及在与反馈电路相关联的诱发响应的稍后分量期间增加的功率,所述反馈电路通常不使用传统的基于幅度的测量来评估。这两种效应都被SAR-152954逆转。这些发现提供了进一步的证据，表明H3R反向激动作用是解决与PAE相关的突触可塑性缺陷的潜在治疗策略。
