Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors
Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors
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DOI：
10.1074/jbc.m004136200
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发表时间：
2000-12-08
影响因子：
4.8
通讯作者：
Valenzuela, CF
中科院分区：
文献类型：
--
作者：
Costa, ET;Olivera, DS;Valenzuela, CF
乙醇对脑配体门控离子通道的作用在酒精相关神经发育障碍和胎儿酒精综合征的病理生理学中具有重要作用。研究表明，N-甲基-D-天冬氨酸 (NMDA) 受体是受产前乙醇暴露影响的配体门控离子通道之一。我们让怀孕的母鼠接触含乙醇的流质饮食，导致血液中的乙醇水平接近大多数州的法定中毒限值 (0.08%)。从这些母鼠的新生后代中制备海马神经元的原代培养物，并在无乙醇培养基中培养 6-7 天后通过膜片钳电生理技术评估 NMDA 受体功能。出乎意料的是，我们没有在全细胞或单通道水平上检测到海马 NMDA 受体功能的任何变化。然而，我们确定胎儿酒精暴露会改变神经类固醇孕烯醇酮硫酸盐和孕烯醇酮半琥珀酸酯的作用，从而增强 NMDA 受体功能。 Western 免疫印迹分析表明，这种变化并不是由于 NMDA 受体亚基表达水平的变化所致。重要的是，子宫内乙醇暴露并不影响抑制NMDA受体功能的神经类固醇的作用，此外，孕烯醇酮硫酸盐对A型γ-氨基丁酸和非NMDA受体功能的作用并未因子宫内乙醇暴露而改变，这表明这种改变是NMDA受体特有的。这些发现很重要，因为它们至少部分地为产前暴露于乙醇和其他形式母体压力的新生大鼠中发现的神经类固醇行为反应的改变提供了合理的机制解释（Zimmerberg, B, 和 McDonald, B, C. (1996) Pharmacol. Biochem. Behav. 55, 541-547）。
The actions of ethanol on brain ligand-gated ion channels have important roles in the pathophysiology of alcohol-related neurodevelopmental disorders and fetal alcohol syndrome. Studies have shown that N-methyl-D-aspartate (NMDA) receptors are among the ligand-gated ion channels affected by prenatal ethanol exposure, We exposed pregnant dams to an ethanol-containing liquid diet that results in blood ethanol levels near the legal intoxication limit in most states (0.08%). Primary cultures of hippocampal neurons were prepared from the neonatal offspring of these dams, and NMDA receptor function was assessed by patch clamp electrophysiological techniques after 6-7 days in culture in ethanol-free media. Unexpectedly, we did not detect any changes in hippocampal NMDA receptor function at either the whole-cell or single-channel levels. However, we determined that fetal alcohol exposure alters the actions of the neurosteroids pregnenolone sulfate and pregnenolone hemisuccinate, which potentiate NMDA receptor function. Western immunoblot analyses demonstrated that this alteration is not due to a change in the expression levels of NMDA receptor subunits. Importantly, in utero ethanol exposure did not affect the actions of neurosteroids that inhibit NMDA receptor function, Moreover, the actions of pregnenolone sulfate on type A gamma -aminobutyric acid and non-NMDA receptor function were unaltered by ethanol exposure in utero, which suggests that the alteration is specific to NMDA receptors. These findings are significant because they provide, at least in part, a plausible mechanistic explanation for the alterations in the behavioral responses to neurosteroids found in neonatal rats prenatally exposed to ethanol and to other forms of maternal stress (Zimmerberg, B,, and McDonald, B, C. (1996) Pharmacol. Biochem. Behav. 55, 541-547).