Conti Alana C, Young Chainllie, Olney John W, Muglia Louis J
Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Neurobiol Dis. 2009 Jan;33(1):111-8. doi: 10.1016/j.nbd.2008.09.022. Epub 2008 Oct 17.
Although a wide range of developmental disabilities following fetal alcohol exposure are observed clinically, the molecular factors that determine the severity of these sequelae remain undefined. In mice exposed to ethanol, deletion of adenylyl cyclases (ACs) 1 and 8 exacerbates the neuroapoptosis that occurs in a prolonged post-treatment period; however, it remains unclear whether AC1 and AC8 are critical to the primary or secondary mechanisms underlying ethanol-induced neurodegeneration. Here we demonstrate that mice lacking AC1 and AC8 (DKO) display significantly increased apoptosis in the striatum, a region sensitive to neuroapoptosis in the acute post-treatment period, compared to WT controls. The enhanced neuroapoptotic response observed in the striatum of DKO mice is accompanied by significant reductions in phosphorylation of known pro-survival proteins, insulin receptor substrate-1 (IRS-1), Akt and extracellular signal-regulated kinases (ERKs). These data suggest that AC1/AC8 are crucial activators of cell survival signaling pathways acutely following ethanol exposure and represent molecular factors that may directly modulate the severity of symptoms associated with Fetal Alcohol Syndrome.
尽管临床上观察到胎儿酒精暴露后会出现多种发育障碍，但决定这些后遗症严重程度的分子因素仍不明确。在暴露于乙醇的小鼠中，腺苷酸环化酶（AC）1和8的缺失会加剧在延长的治疗后期发生的神经细胞凋亡；然而，AC1和AC8对于乙醇诱导的神经变性的主要或次要机制是否至关重要仍不清楚。在这里，我们证明，与野生型对照相比，缺乏AC1和AC8（双敲除，DKO）的小鼠在纹状体中显示出明显增加的细胞凋亡，纹状体是治疗后急性期对神经细胞凋亡敏感的区域。在DKO小鼠纹状体中观察到的增强的神经细胞凋亡反应伴随着已知的促生存蛋白胰岛素受体底物-1（IRS-1）、Akt和细胞外信号调节激酶（ERK）磷酸化的显著降低。这些数据表明，AC1/AC8是乙醇暴露后急性期细胞生存信号通路的关键激活剂，并且代表了可能直接调节与胎儿酒精综合征相关症状严重程度的分子因素。
