Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois.
Glia. 2014 Feb;62(2):259-71. doi: 10.1002/glia.22604. Epub 2013 Dec 6.
In utero ethanol exposure causes fetal alcohol spectrum disorders, associated with reduced brain plasticity; the mechanisms of these effects are not well understood, particularly with respect to glial involvement. Astrocytes release factors that modulate neurite outgrowth. We explored the hypothesis that ethanol inhibits neurite outgrowth by increasing the levels of inhibitory chondroitin sulfate proteoglycans (CSPGs) in astrocytes. Astrocyte treatment with ethanol inhibited the activity of arylsulfatase B (ARSB), the enzyme that removes sulfate groups from chondroitin-4-sulfate (C4S) and triggers the degradation of C4S, increased total sulfated glycosaminoglycans (GAGs), C4S, and neurocan core-protein content and inhibited neurite outgrowth in neurons cocultured with ethanol-treated astrocytes in vitro, effects reversed by treatment with recombinant ARSB. Ethanol also inhibited ARSB activity and increased sulfate GAG and neurocan levels in the developing hippocampus after in vivo ethanol exposure. ARSB silencing increased the levels of sulfated GAGs, C4S, and neurocan in astrocytes and inhibited neurite outgrowth in cocultured neurons, indicating that ARSB activity directly regulates C4S and affects neurocan expression. In summary, this study reports two major findings: ARSB modulates sulfated GAG and neurocan levels in astrocytes and astrocyte-mediated neurite outgrowth in cocultured neurons; and ethanol inhibits the activity of ARSB, increases sulfated GAG, C4S, and neurocan levels, and thereby inhibits astrocyte-mediated neurite outgrowth. An unscheduled increase in CSPGs in the developing brain may lead to altered brain connectivity and to premature decrease in neuronal plasticity and therefore represents a novel mechanism by which ethanol can exert its neurodevelopmental effects.
子宫内乙醇暴露会导致胎儿酒精谱系障碍，与脑可塑性降低有关；这些影响的机制尚不清楚，特别是与神经胶质细胞的参与有关。星形胶质细胞释放调节神经突生长的因子。我们探讨了这样一个假设，即乙醇通过增加星形胶质细胞中抑制性硫酸软骨素蛋白聚糖 (CSPGs) 的水平来抑制神经突生长。用乙醇处理星形胶质细胞会抑制芳基硫酸酯酶 B (ARSB) 的活性，这种酶从软骨素-4-硫酸盐 (C4S) 上去除硫酸盐基团，并触发 C4S 的降解，增加总硫酸化糖胺聚糖 (GAGs)、C4S 和神经蛋白核心蛋白的含量，并抑制体外与乙醇处理的星形胶质细胞共培养的神经元的神经突生长，用重组 ARSB 处理可逆转这些作用。乙醇还抑制体内乙醇暴露后发育中的海马中的 ARSB 活性和硫酸盐 GAG 和神经蛋白的水平。ARSB 沉默增加了星形胶质细胞中硫酸化 GAG、C4S 和神经蛋白的水平，并抑制了共培养神经元中的神经突生长，表明 ARSB 活性直接调节 C4S 并影响神经蛋白的表达。总之，这项研究报告了两个主要发现：ARSB 调节星形胶质细胞中硫酸化 GAG 和神经蛋白的水平以及共培养神经元中星形胶质细胞介导的神经突生长；乙醇抑制 ARSB 的活性，增加硫酸化 GAG、C4S 和神经蛋白的水平，从而抑制星形胶质细胞介导的神经突生长。发育中的大脑中 CSPGs 的意外增加可能导致大脑连接的改变和神经元可塑性的过早降低，因此代表了乙醇发挥其神经发育作用的一种新机制。
