Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Alcohol. 2021 Nov;96:43-53. doi: 10.1016/j.alcohol.2021.07.003. Epub 2021 Aug 4.
Fetal alcohol spectrum disorders (FASD) are alarmingly common, result in significant personal and societal loss, and there are no effective treatments for these disorders. Cerebellar neuropathology is common in FASD and can cause impaired cognitive and motor function. The current study evaluates the effects of ethanol on oligodendrocyte-lineage cells, as well as molecules that modulate oligodendrocyte differentiation and function in the cerebellum in a postnatal mouse model of FASD. Neonatal mice were treated with ethanol from P4-P9 (postnatal day), the cerebellum was isolated at P10, and mRNAs encoding oligodendrocyte-associated molecules were quantitated by qRT-PCR. Our studies demonstrated that ethanol significantly reduced the expression of markers for multiple stages of oligodendrocyte maturation, including oligodendrocyte precursor cells, pre-myelinating oligodendrocytes, and mature myelinating oligodendrocytes. Additionally, we determined that ethanol significantly decreased the expression of molecules that play critical roles in oligodendrocyte differentiation. Interestingly, we also observed that ethanol significantly reduced the expression of myelin-associated inhibitors, which may act as a compensatory mechanism to ethanol toxicity. Furthermore, we demonstrate that ethanol alters the expression of a variety of molecules important in oligodendrocyte function and myelination. Collectively, our studies increase our understanding of specific mechanisms by which ethanol modulates myelination in the developing cerebellum, and potentially identify novel targets for FASD therapy.
胎儿酒精谱系障碍（FASD）非常普遍，会给个人和社会造成重大损失，而且目前尚无针对这些疾病的有效治疗方法。小脑神经病理学在 FASD 中很常见，可导致认知和运动功能受损。本研究在 FASD 的新生小鼠模型中评估了乙醇对少突胶质细胞谱系细胞的影响，以及调节小脑内少突胶质细胞分化和功能的分子的影响。新生小鼠在 P4-P9（出生后第 4-9 天）期间接受乙醇处理，在 P10 时分离小脑，并通过 qRT-PCR 定量分析编码少突胶质细胞相关分子的 mRNAs。我们的研究表明，乙醇显著降低了多个少突胶质细胞成熟阶段的标志物的表达，包括少突胶质前体细胞、前髓鞘化少突胶质细胞和成熟髓鞘化少突胶质细胞。此外，我们确定乙醇显著降低了在少突胶质细胞分化中起关键作用的分子的表达。有趣的是，我们还观察到乙醇显著降低了髓鞘相关抑制剂的表达，这可能是一种对抗乙醇毒性的代偿机制。此外，我们还证明，乙醇改变了与少突胶质细胞功能和髓鞘形成有关的多种分子的表达。总的来说，我们的研究增加了我们对乙醇在发育中小脑髓鞘形成中调节特定机制的理解，并可能为 FASD 治疗确定新的靶点。
