Xu Ziyue, Shi Jichun, Liu Runming, Li Zhehao, Xu Shuangxiang, Gong Hao, Fu Mingyue, Xu Hongyu, Yu Shuangqi, Liu Junhui, Wu Huiqing, Li Xiang, Liu Sha, Wei Wei
Brain Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane 4702, Australia.
Brain Res Bull. 2025 Jan;220:111167. doi: 10.1016/j.brainresbull.2024.111167. Epub 2024 Dec 13.
Circular RNAs (circRNAs) are novel class of stable regulatory RNAs abundantly expressed in the brain. However, their role in fear extinction (EXT) memory remains largely unexplored. To investigate the mechanisms of Circular Special AT-rich Sequence Binding Protein 2 (circSatb2) in EXT memory, we constructed a lentivirus overexpressing circSatb2 and injected it into the infralimbic prefrontal cortex (ILPFC) of the mouse brain. Following extinction training and subsequent testing, we observed an essential role of circSatb2 in this dynamic process. RNA sequencing (RNA-seq) and bioinformatics analyses revealed that circSatb2 enhances the transcription of Roundabout Guidance Receptor 3 (Robo3), a key gene implicated in axon guidance and synaptic plasticity, which was validated by RT-qPCR. Neuronal morphology was assessed using confocal microscopy to determine changes in dendritic spine density. Our results demonstrated that circSatb2 significantly enhances Robo3 transcription, leading to increased dendritic spine formation and improved synaptic plasticity. In conclusion, circSatb2 promotes the formation of EXT memory by upregulating Robo3 transcription and enhancing synaptic plasticity. These findings position circSatb2 as a potential therapeutic target for disorders associated with memory impairment.
环状RNA（circRNAs）是一类在大脑中大量表达的新型稳定调控RNA。然而，它们在恐惧消退（EXT）记忆中的作用在很大程度上仍未被探索。为了研究环状富含AT序列结合蛋白2（circSatb2）在EXT记忆中的作用机制，我们构建了过表达circSatb2的慢病毒，并将其注射到小鼠大脑的边缘下前额叶皮质（ILPFC）。经过消退训练和随后的测试，我们观察到circSatb2在这个动态过程中起着至关重要的作用。RNA测序（RNA-seq）和生物信息学分析表明，circSatb2增强了Roundabout导向受体3（Robo3）的转录，Robo3是一个与轴突导向和突触可塑性有关的关键基因，这一点通过RT-qPCR得到了验证。使用共聚焦显微镜评估神经元形态，以确定树突棘密度的变化。我们的结果表明，circSatb2显著增强Robo3转录，导致树突棘形成增加和突触可塑性改善。总之，circSatb2通过上调Robo3转录和增强突触可塑性促进EXT记忆的形成。这些发现将circSatb2定位为与记忆障碍相关疾病的潜在治疗靶点。
