Neuroscience Graduate Program, Virginia Commonwealth University, Richmond, Virginia, USA.
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
Addict Biol. 2021 Jul;26(4):e13019. doi: 10.1111/adb.13019. Epub 2021 Feb 3.
Identifying mechanisms underlying alcohol-related behaviors could provide important insights regarding the etiology of alcohol use disorder. To date, most genetic studies on alcohol-related behavior in model organisms have focused on neurons, leaving the causal roles of glial mechanisms less comprehensively investigated. Here, we report our studies on the role of Tyrosine decarboxylase 2 (Tdc2), which converts tyrosine to the catecholamine tyramine, in glial cells in Drosophila alcohol sedation. Using genetic approaches that drove transgene expression constitutively in all glia, constitutively in astrocytes and conditionally in glia during adulthood, we found that knockdown and overexpression of Tdc2, respectively, increased and decreased the sensitivity to alcohol sedation in flies. Manipulation of the genes tyramine β-hydroxylase and tyrosine hydroxylase, which respectively synthesize octopamine and dopamine from tyramine and tyrosine, had no discernable effect on alcohol sedation, suggesting that Tdc2 affects alcohol sedation by regulating tyramine production. We also found that knockdown of the vesicular monoamine transporter (VMAT) and disruption of the SNARE complex in all glia or selectively in astrocytes increased sensitivity to alcohol sedation and that both VMAT and the SNARE complex functioned downstream of Tdc2. Our studies support a model in which the synthesis of tyramine and vesicle-mediated release of tyramine from adult astrocytes regulates alcohol sedation in Drosophila. Considering that tyramine is functionally orthologous to norepinephrine in mammals, our results raise the possibility that gliotransmitter synthesis release could be a conserved mechanism influencing behavioral responses to alcohol as well as alcohol use disorder.
确定与酒精相关行为相关的机制可以为酒精使用障碍的病因提供重要的见解。迄今为止，大多数关于模式生物中与酒精相关行为的遗传研究都集中在神经元上，而胶质机制的因果作用则没有得到全面的研究。在这里，我们报告了我们在酪氨酸脱羧酶 2（Tdc2）在果蝇酒精镇静中的胶质细胞中的作用的研究。使用遗传方法，我们在所有胶质细胞中持续表达转基因，在成年后持续在星形胶质细胞中表达，并且条件性地在胶质细胞中表达，我们发现 Tdc2 的敲低和过表达分别增加和降低了果蝇对酒精镇静的敏感性。操纵 tyramine β-hydroxylase 和 tyrosine hydroxylase 基因，它们分别从 tyramine 和 tyrosine 合成章鱼胺和多巴胺，对酒精镇静没有明显影响，这表明 Tdc2 通过调节 tyramine 的产生来影响酒精镇静。我们还发现，在所有胶质细胞或选择性地在星形胶质细胞中敲低囊泡单胺转运蛋白（VMAT）和破坏 SNARE 复合物会增加对酒精镇静的敏感性，并且 VMAT 和 SNARE 复合物都在 Tdc2 下游发挥作用。我们的研究支持这样一种模型，即 tyramine 的合成和成年星形胶质细胞中 tyramine 的囊泡介导释放调节果蝇的酒精镇静。考虑到 tyramine 在功能上与哺乳动物中的去甲肾上腺素同源，我们的结果提出了这样一种可能性，即神经递质合成释放可能是一种保守机制，影响对酒精以及酒精使用障碍的行为反应。
