Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.
School of Psychological Sciences, Monash University, Melbourne, VIC, 3800, Australia.
Mol Neurobiol. 2021 Apr;58(4):1330-1344. doi: 10.1007/s12035-020-02197-6. Epub 2020 Nov 9.
MicroRNAs are known to be critical regulators of neuronal plasticity. The highly conserved, hypoxia-regulated microRNA-210 (miR-210) has been shown to be associated with long-term memory in invertebrates and dysregulated in neurodevelopmental and neurodegenerative disease models. However, the role of miR-210 in mammalian neuronal function and cognitive behaviour remains unexplored. Here we generated Nestin-cre-driven miR-210 neuronal knockout mice to characterise miR-210 regulation and function using in vitro and in vivo methods. We identified miR-210 localisation throughout neuronal somas and dendritic processes and increased levels of mature miR-210 in response to neural activity in vitro. Loss of miR-210 in neurons resulted in higher oxidative phosphorylation and ROS production following hypoxia and increased dendritic arbour density in hippocampal cultures. Additionally, miR-210 knockout mice displayed altered behavioural flexibility in rodent touchscreen tests, particularly during early reversal learning suggesting processes underlying updating of information and feedback were impacted. Our findings support a conserved, activity-dependent role for miR-210 in neuroplasticity and cognitive function.
微小 RNA 被认为是神经元可塑性的关键调节因子。高度保守的缺氧调节微小 RNA-210（miR-210）已被证明与无脊椎动物的长期记忆有关，并在神经发育和神经退行性疾病模型中失调。然而，miR-210 在哺乳动物神经元功能和认知行为中的作用仍未得到探索。在这里，我们生成了 Nestin-cre 驱动的 miR-210 神经元敲除小鼠，以使用体外和体内方法来表征 miR-210 的调节和功能。我们确定了 miR-210 在神经元胞体和树突突起中的定位，并在体外观察到神经活动后成熟 miR-210 的水平增加。神经元中 miR-210 的缺失导致缺氧后氧化磷酸化和 ROS 产生增加，以及海马培养物中的树突分支密度增加。此外，miR-210 敲除小鼠在啮齿动物触摸屏测试中表现出行为灵活性的改变，特别是在早期反转学习中，这表明信息更新和反馈的过程受到了影响。我们的研究结果支持 miR-210 在神经可塑性和认知功能中的保守、活性依赖性作用。
