AMPA受体介导VGF释放参与GLYX-13抗抑郁作用的分子机制

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.

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。

我们发现敲减神经肽VGF通过TrkB调控BICC1，AMPA受体转运诱导抑郁样行为并阻断氯胺酮快速抗抑郁作用。进一步发现VGF衍生肽TLQP-62快速抗抑郁作用作用机制与Ketamine共享TrkB/mTOR/BICC1信号通路及其AMPA受体转运机制。我们发现GLYX-13快速抗抑郁作用不仅仅依赖于AKT介导的mTOR/VGF信号通路，而且依赖于ERK的信号通路。并且我们证实VGF介导的信号通路参与GLYX-13快速抗抑郁作用。针对何种机制介导了抑郁症发病中BDNF与VGF的下调及其AMPA受体转运障碍，我们发现首发重症抑郁症患者外周血中BICC1表达显著增高并伴随BDNF及VGF的水平降低，并且进一步发现BICC1过表达诱导Dvl2/GSK3β/mTOR信号通路及AMPA受体转运障碍。基于大量研究表明AMPA受体可能是快速抗抑郁的关键分子，结合我们发现东莨菪碱快速抗抑郁中突触前VGLUT1调控Glu释放及其突触后AMPA受体的激活、BDNF与VGF的快速释放及其GluA1转运参与其中。我们提出基于AMPA受体正向别构调节作为快速抗抑郁作用的关键分子靶标，我们率先发现新型AMPA受体正向别构调节剂PF-4778574快速抗抑郁作用依赖于AMPA受体介导的VGF/BDNF/ AKT信号通路。