m6A识别蛋白YTHDF1在长时程抑制（LTD）和学习记忆中的作用及分子机制

长时程突触可塑性是学习记忆的基础，其维持依赖蛋白合成。m6A修饰能通过其识别蛋白调控mRNA的命运影响蛋白合成。最新研究发现，m6A识别蛋白YTHDF1在学习刺激后能促进靶标mRNA翻译从而影响学习记忆，但其功能如何受刺激调控尚不清楚。申请人前期实验发现，小鼠接受学习刺激后，YTHDF1会特异地结合Gαq，提示G蛋白可能参与调控。Gαq主要调节mGluR-LTD，而YTHDF1是否调控LTD未见报道。因此，本项目将利用学习记忆相关行为分析、电生理记录、药理学干扰和基因编辑等方法，对YTHDF1-Gαq互作在mGluR-LTD和学习记忆中的作用及分子机制进行探索：①明确YTHDF1是否是Gαq的效应蛋白且调控mGluR-LTD；②明确YTHDF1-Gαq互作参与mGluR-LTD和学习记忆功能的详细机制。本项目将完善我们对学习记忆调控机制的理解，并有可能发现学习记忆障碍相关疾病的干预新靶点。

The major physiological basis of learning and memory is long-term synaptic plasticity, the maintenance of which depends on protein synthesis. m6A modification can function through its reader protein to regulate mRNA fate and consequently affect protein synthesis. Our recent research found that, m6A can facilitate learning and memory through its reader protein YTHDF1, which can promote the translation of target mRNA in response to learning stimulus. However, the molecular mechanism by which stimulus modulates YTHDF1 function remains unknown. In my preliminary proteomic analysis, I found that YTHDF1 specifically interacts with Gαq when the mouse receives learning stimulus, suggesting that the function of YTHDF1 may be regulated by G-protein signaling. Gαq is mainly involved in regulating mGluR-dependent LTD (mGluR-LTD), but whether YTHDF1 regulates LTD has not been reported yet. Therefore, this project will focus on the YTHDF1-Gαq interaction to explore its role and the underlying molecular mechanism in mGluR-LTD as well as in learning and memory: ① To determine whether YTHDF1 is an effector of Gαq and regulates mGluR-LTD; ② To determine the detailed mechanism underlying the role of YTHDF1-Gαq interaction in mGluR-LTD as well as in learning and memory. Various techniques, including learning and memory-related behavioral analysis, electrophysiological recording, pharmacological interference and CRISPR-Cas9 gene editing, will be used. This project will deepen our understanding of the regulatory mechanisms of learning and memory, and may help to find new therapeutic strategies or targets for relevant disease.