Clark Kevin D, Lee Colin, Gillette Rhanor, Sweedler Jonathan V
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
ACS Cent Sci. 2021 Jul 28;7(7):1183-1190. doi: 10.1021/acscentsci.1c00351. Epub 2021 Jul 18.
Subtle changes in the landscape of post-transcriptional modifications have emerged as putative regulators of central nervous system plasticity and activity-induced protein synthesis. However, simultaneous characterization of multiple RNA modifications and their covariation during learning and memory paradigms has been impeded by the complexity of animal models and lack of untargeted approaches for identifying pathway-relevant RNA modifications in small-volume samples. Here, we used mass spectrometry to profile spatiotemporal changes in dozens of neuronal RNA modifications in during behavioral sensitization of a simple defensive reflex. Unique RNA modification patterns were observed in the major ganglia of trained and naı̇ve animals, with two tRNA modifications, namely, 5-methoxycarbonylmethyl-2-thiouridine (mcmsU) and 1-methyladenosine (mA), at significantly higher levels in trained subjects. We report that tRNAs, and their modifications, correlate with increased polyglutamine synthesis and excitability in neurons, characterizing the first link between noncoding RNA modifications and non-associative learning.
转录后修饰景观的细微变化已成为中枢神经系统可塑性和活动诱导蛋白合成的假定调节因子。然而,在学习和记忆范式中对多种RNA修饰及其共变进行同时表征,受到动物模型复杂性以及缺乏用于在小体积样本中鉴定与通路相关的RNA修饰的非靶向方法的阻碍。在此,我们使用质谱分析在简单防御反射的行为敏化过程中数十种神经元RNA修饰的时空变化。在受过训练和未受过训练的动物的主要神经节中观察到独特的RNA修饰模式,其中两种tRNA修饰,即5-甲氧羰基甲基-2-硫尿苷(mcmsU)和1-甲基腺苷(mA),在受过训练的动物中水平显著更高。我们报告说,tRNA及其修饰与神经元中多聚谷氨酰胺合成增加和兴奋性相关,这是首次描述非编码RNA修饰与非联想学习之间的联系。