Karaçay Bahri, Li Shenglan, Bonthius Daniel J
Division of Child Neurology, Department of Pediatrics, 200 Hawkins Dr., University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Alcohol Clin Exp Res. 2008 Aug;32(8):1439-50. doi: 10.1111/j.1530-0277.2008.00720.x. Epub 2008 Jun 28.
Alcohol abuse during pregnancy injures the fetal brain. One of alcohol's most important neuroteratogenic effects is neuronal loss. Rat models have shown that the cerebellum becomes less vulnerable to alcohol-induced neuronal death as it matures. We determined if maturation-dependent alcohol resistance occurs in mice and compared patterns of gene expression during the alcohol resistant and sensitive periods.
Neonatal mice received alcohol daily over postnatal day (PD) 2 to 4 or PD8 to 10. Purkinje cells and granule cells were quantified on PD25. The temporal expression patterns of 4 neuro-developmental genes and 3 neuro-protective genes in the cerebellum were determined daily over PD0 to 15 to determine how gene expression changes as the cerebellum transitions from alcohol-vulnerable to alcohol-resistant. The effect of alcohol on expression of these genes was determined when the cerebellum is alcohol sensitive (PD4) and resistant (PD10).
Purkinje and granule cells were vulnerable to alcohol-induced death at PD2 to 4, but not at PD8 to 10. Acquisition of maturation-dependent alcohol resistance coincided with changes in the expression of neurodevelopmental genes. The vulnerability of cerebellar neurons to alcohol toxicity declined in parallel with decreasing levels of Math1 and Cyclin D2, markers of immature granule cells. Likewise, the rising resistance to alcohol toxicity paralleled increasing levels of GABA alpha-6 and Wnt-7a, markers of mature granule neurons. Expression of growth factors and genes with survival promoting function (IGF-1, BDNF, and cyclic AMP response element binding protein) did not rise as the cerebellum transitioned from alcohol-vulnerable to alcohol-resistant. All 3 were expressed at substantial levels during the vulnerable period and were not expressed at higher levels later. Acute alcohol exposure altered the expression of neurodevelopmental genes and growth factor genes when administered either during the alcohol vulnerable period or resistant period. However, the patterns in which gene expression changed varied among the genes and depended on timing of alcohol administration.
Mice have a temporal window of vulnerability in the first week of life, during which cerebellar neurons are more sensitive to alcohol toxicity than during the second week. Expression of genes governing neuronal maturation changes in synchrony with the acquisition of alcohol resistance. Growth factors do not rise as the cerebellum transitions from alcohol-vulnerable to alcohol-resistant. Thus, a process intrinsic to neuronal maturation, rather than rising levels of growth factors, likely underlies maturation-dependent alcohol resistance.
孕期酗酒会损害胎儿大脑。酒精最重要的神经致畸作用之一是神经元丢失。大鼠模型显示，小脑在成熟过程中对酒精诱导的神经元死亡的易感性降低。我们确定了小鼠是否存在成熟依赖性酒精抗性，并比较了酒精抗性期和敏感期的基因表达模式。
新生小鼠在出生后第2至4天或第8至10天每天接受酒精处理。在出生后第25天对浦肯野细胞和颗粒细胞进行定量。在出生后第0至15天每天测定小脑中4种神经发育基因和3种神经保护基因的时间表达模式，以确定随着小脑从酒精易感性转变为酒精抗性，基因表达如何变化。当小脑对酒精敏感（出生后第4天）和具有抗性（出生后第10天）时，确定酒精对这些基因表达的影响。
浦肯野细胞和颗粒细胞在出生后第2至4天易受酒精诱导的死亡影响，但在出生后第8至10天则不然。成熟依赖性酒精抗性的获得与神经发育基因表达的变化同时发生。小脑神经元对酒精毒性的易感性随着未成熟颗粒细胞标志物Math1和细胞周期蛋白D2水平的降低而平行下降。同样，对酒精毒性的抗性增加与成熟颗粒神经元标志物GABAα-6和Wnt-7a水平的增加平行。随着小脑从酒精易感性转变为酒精抗性，生长因子和具有促存活功能的基因（胰岛素样生长因子-1、脑源性神经营养因子和环磷酸腺苷反应元件结合蛋白）的表达并未升高。这三种基因在敏感期均大量表达，后期并未更高水平表达。在酒精敏感期或抗性期给予急性酒精暴露会改变神经发育基因和生长因子基因的表达。然而，基因表达变化的模式因基因而异，并取决于酒精给药的时间。
小鼠在出生后的第一周有一个易受影响的时间窗口，在此期间小脑神经元对酒精毒性比第二周更敏感。控制神经元成熟的基因表达与酒精抗性的获得同步变化。随着小脑从酒精易感性转变为酒精抗性，生长因子并未升高。因此，神经元成熟的内在过程，而非生长因子水平的升高，可能是成熟依赖性酒精抗性的基础。
