Mameli Manuel, Valenzuela C Fernando
Department of Neurosciences, University of New Mexico, HSC, Albuquerque, NM 87131, USA.
Eur J Neurosci. 2006 Feb;23(3):835-9. doi: 10.1111/j.1460-9568.2006.04597.x.
Fetal ethanol exposure persistently affects hippocampal circuits leading to learning and memory disabilities. Although the mechanisms responsible for these effects are not fully understood, several studies implicate neurosteroids as mediators of the actions of ethanol. A neurosteroid that appears to be critical for the fetal actions of ethanol is pregnenolone sulfate (PREGS). We found that chronic prenatal ethanol exposure increases PREGS levels in the fetal brain and that an endogenous PREGS-like neurosteroid strengthens excitatory transmission in the neonatal hippocampus. Therefore, we hypothesized that ethanol could affect synaptic transmission in the developing hippocampus in a PREGS-dependent manner. We used patch-clamp electrophysiological techniques and found that 50 mm ethanol strengthens AMPA receptor-mediated transmission in the CA1 region by reducing the failure rate of low-efficacy synapses. This effect was age-dependent and was occluded by application of exogenous PREGS. An anti-PREGS antibody scavenger and blockade of PREGS synthesis prevented the effect of ethanol. These data indicate that the deleterious effects of ethanol on hippocampal development are mediated in part by alterations in neurosteroid production, which results in premature stabilization of excitatory synapses.
胎儿暴露于乙醇会持续影响海马回路，导致学习和记忆障碍。尽管导致这些影响的机制尚未完全了解，但多项研究表明神经甾体是乙醇作用的介导物。一种似乎对乙醇的胎儿作用至关重要的神经甾体是硫酸孕烯醇酮（PREGS）。我们发现，孕期长期暴露于乙醇会增加胎儿大脑中的PREGS水平，并且一种内源性PREGS样神经甾体可增强新生海马体中的兴奋性传递。因此，我们推测乙醇可能以PREGS依赖的方式影响发育中的海马体中的突触传递。我们使用膜片钳电生理技术，发现50毫米乙醇通过降低低效突触的失败率来增强CA1区域中AMPA受体介导 的传递。这种效应具有年龄依赖性，并且通过应用外源性PREGS而被阻断。抗PREGS抗体清除剂和PREGS合成的阻断可防止乙醇的作用。这些数据表明，乙醇对海马体发育的有害影响部分是由神经甾体产生的改变介导的，这导致兴奋性突触过早稳定。
