寻找快速抗抑郁剂是当今抑郁症研究的热点与难点。研究发现GLYX-13作为NMDA受体甘氨酸结合位点部分激动剂也依赖AMPA受体发挥快速抗抑郁作用。我们首次报道神经肽VGF通过PI3K/AKT/mTORC1信号通路参与GLYX-13抗抑郁作用，并证实VGF衍生肽TLQP-62调控TrkB发挥抗抑郁作用。但是，GLXY-13如何介导AMPA受体调控VGF的释放并进一步作用于TrkB/PI3K/AKT/mTORC1信号通路在抗抑郁中的分子机制尚不明确。本项目拟采用原代海马神经元，慢性不可预见性应激大鼠及VGF基因敲除小鼠模型，结合分子、细胞、电生理、行为学及药理学手段，阐明GLYX-13调控VGF释放的机制，并深入研究GLYX-13调控抑郁样行为、海马神经发生与突触发生中VGF的参与作用及分子机制。该项目将为深入阐释GLYX-13抗抑郁作用的分子机制及临床应用GLYX-13抗抑郁奠定理论基础。

Looking for new antidepressant agents with novel mechanisms that have faster onset of action and greater efficacy is hot and hard points of present depression research. GLYX-13, a functional partial agonist of NMDA receptor glycine-site produces rapid onset antidepressant-like effects also dependent on AMPA receptor activation. Previously, we have provided the first evidence for the critical role of neuropeptide VGF (non-acronymic) -mediated PI3K/AKT/mTORC1 signaling involved in the fast-acting antidepressant-like activity of GLYX-13. Additionally, our previous results also highlight that the activation of TrkB participates inthe antidepressant-like effects of VGF-derived peptide TLQP62. However, the mechanisms underlying the release of VGF in the hippocampus modulated by AMPA receptor, as well as the interaction between VGF release and the downstream PI3K/AKT/mTORC1 signaling in antidepressant-like effects of GLYX-13 remain poorly characterized. Herein, by combining the original generation of cultured hippocampal neurons, the chronic unpredictable stress (CUS) induce rats model and VGF knock out (VGF+/-) mice with molecular, cellular, and behavioral approaches, we aim to establish how to regulate the VGF release in the hippocampus by GLYX-13 in antidepressant-like activity process, with a long-term goal to understand the molecular mechanisms of VGF involved in the regulation of GLYX-13 in hippocampal neurogenesis and synaptogenesis. Our results may contribute to clarify the precise mechanisms underlying the antidepressant-like action of GLYX-13 and further to bring new insights to the GLYX-13.in depression and in antidepressant development.