Ganesh Ambigapathy, Talus J. McCowan, Lucia Carvelli
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引用次数: 0
Abstract
The dopamine transporter (DAT) is a transmembrane protein that regulates dopamine (DA) neurotransmission by binding to and moving DA from the synaptic cleft back into the neurons. Besides moving DA and other endogenous monoamines, DAT is also a neuronal carrier for exogenous compounds such as the psychostimulant amphetamine (Amph), and several studies have shown that Amph-induced behaviors require a functional DAT. Here, we demonstrate that exposure to Amph during early development causes behavioral, functional, and epigenetic modifications at the Caenorhabditis elegans DAT gene homolog, dat-1, in C. elegans offspring. Specifically, we show that, while embryos exposed to Amph generate adults that produce offspring with no obvious behavioral alterations, both adults and offspring exhibit an increased behavioral response when challenged with Amph. Our functional studies suggest that a decrease in DAT-1 expression underlies the increased behavioral response to Amph seen in offspring. Moreover, our epigenetic data suggest that histone methylation is a mechanism utilized by Amph to maintain changes in DAT-1 expression in offspring. Taken together, our data reveal that Amph, by altering the epigenetic landscape of DAT, propagates long-lasting functional and behavioral changes in offspring.
多巴胺转运体(DAT)是一种跨膜蛋白,它通过与多巴胺结合并将其从突触间隙移回神经元来调节多巴胺(DA)的神经传递。除了移动 DA 和其他内源性单胺类物质外,DAT 还是精神兴奋剂苯丙胺(Amph)等外源性化合物的神经元载体,多项研究表明,苯丙胺诱导的行为需要功能性 DAT。在这里,我们证明了在早期发育过程中暴露于安非他明会导致秀丽隐杆线虫 DAT 基因同源物 dat-1 的后代发生行为、功能和表观遗传学改变。具体来说,我们发现,当胚胎暴露于Amph时,其产生的成虫和后代没有明显的行为改变,而当成虫和后代受到Amph的挑战时,其行为反应都会增加。我们的功能研究表明,DAT-1表达的减少是后代对Amph行为反应增强的基础。此外,我们的表观遗传学数据表明,组蛋白甲基化是 Amph 用来维持后代中 DAT-1 表达变化的一种机制。总之,我们的数据揭示了安弗通过改变 DAT 的表观遗传景观,在后代中传播持久的功能和行为变化。
期刊介绍:
Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.