Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Neuroscience. 2010 Nov 10;170(4):1328-44. doi: 10.1016/j.neuroscience.2010.07.059. Epub 2010 Aug 5.
Ectopic neurons are often found in the brains of fetal alcohol spectrum disorders (FASD) and fetal alcohol syndrome (FAS) patients, suggesting that alcohol exposure impairs neuronal cell migration. Although it has been reported that alcohol decreases the speed of neuronal cell migration, little is known about whether alcohol also affects the turning of neurons. Here we show that ethanol exposure inhibits the turning of cerebellar granule cells in vivo and in vitro. First, in vivo studies using P10 mice demonstrated that a single intraperitoneal injection of ethanol not only reduces the number of turning granule cells but also alters the mode of turning at the EGL-ML border of the cerebellum. Second, in vitro analysis using microexplant cultures of P0-P3 mouse cerebella revealed that ethanol directly reduces the frequency of spontaneous granule cell turning in a dose-dependent manner. Third, the action of ethanol on the frequency of granule cell turning was significantly ameliorated by stimulating Ca(2+) and cGMP signaling or by inhibiting cAMP signaling. Taken together, these results indicate that ethanol affects the frequency and mode of cerebellar granule cell turning through alteration of the Ca(2+) and cyclic nucleotide signaling pathways, suggesting that the abnormal allocation of neurons found in the brains of FASD and FSA patients results, at least in part, from impaired turning of immature neurons by alcohol.
在胎儿酒精谱系障碍 (FASD) 和胎儿酒精综合征 (FAS) 患者的大脑中经常发现异位神经元,这表明酒精暴露会损害神经元细胞迁移。尽管有报道称酒精会降低神经元细胞迁移的速度,但对于酒精是否也会影响神经元的转向知之甚少。在这里,我们表明乙醇暴露会抑制小脑颗粒细胞在体内和体外的转向。首先,使用 P10 小鼠的体内研究表明,单次腹腔注射乙醇不仅会减少转向颗粒细胞的数量,还会改变小脑外颗粒层 - 分子层边界处的转向模式。其次,使用 P0-P3 小鼠小脑的微外植体培养进行的体外分析表明,乙醇以剂量依赖的方式直接降低自发颗粒细胞转向的频率。第三,通过刺激 Ca(2+) 和 cGMP 信号或抑制 cAMP 信号,乙醇对颗粒细胞转向频率的作用明显改善。总之,这些结果表明,乙醇通过改变 Ca(2+) 和环核苷酸信号通路来影响小脑颗粒细胞转向的频率和模式,这表明在 FASD 和 FAS 患者大脑中发现的神经元异常分配至少部分是由于酒精对未成熟神经元转向的损害所致。