抑郁症发病率逐年增高。NMDAR和AMPAR跨膜转运功能受损是抑郁发病的重要病理基础，阻断其功能的抗抑郁药研发滞后。NMDAR和AMPAR上游调控分子有望成为新型抗抑郁靶点，但尚待研究。前期研究发现抑郁小鼠下丘脑EphB2上调及其配体EphrinB1下调、NMDAR亚基GluN2A上调；生信分析表明EphB2/EphrinB1调控NMDAR和AMPAR；敲除EphB2抑制神经元凋亡。推测：EphB2/EphrinB1可调节NMDAR和AMPAR介导的谷氨酸能传递效能，活化下游通路致突触可塑性损伤和神经发生降低，诱发抑郁行为。本研究拟通过体外实验及抑郁模型验证，敲除及激活EphB2，检测AKT等通路关键节点表达水平；干预关键节点，评估谷氨酸能传递、突触可塑性和神经发生及抑郁样行为，揭示EphB2/EphrinB1调节谷氨酸能传递效能致神经发生和突触可塑性损伤的机制，阐明抑郁机理，探索治疗靶点

The incidence of depression increases in patients with inflammation recently. N-methyl-D-aspartic acid receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the culprit of dysfunctions of glutamatergic transmission, neurogenesis and neuroplasticity, is one of important pathophysiological mechanisms for depression. Because of widely distribution and functionally complex of NMDAR and AMPAR, the development of antidepressants that target NMDAR and AMPAR faces many challenges. It is vital for the development of antidepressants that upstream modulates NMDAR and AMPAR as potential anti-depression medicine. We adopted mouse model of depression. A series of studies were carried out to search for upstream regulatory molecules of NMDAR and AMPAR. Firstly, the integration of metabolomics-proteomics study showed that the hypothalamus EphB2 and GluN2A subunit of NMDAR were increased. Ephrin-B1, ligand of EphB2, was decreased. Secondly, down-regulation EphB2 antagonized neuronal apoptosis in cellular experiments. Thirdly, bioinformatics analysis revealed EphB2 directly interacted with NMDAR and AMPAR. As NMDAR and AMPAR regulatory molecules, the effect of EphB2/Ephrin-B1 in the depression remains unclear. We hypothesized that activated EphB2/Ephrin-B1 modifies NMDAR or AMPAR-mediated glutamatergic transmission efficiency, results in impairing synaptic plasticity and weakening neurogenesis by downstream signaling pathway. This is the core molecular mechanism of depression. In present study, the EphB2 knockout mice were utilized. The expression of AKT, ERK, MAPK, CREB, neurotrophin pathway was detected in the primary neuron and the depressed mice. Further, intervention in these pathways was conducted to investigate the changes in NMDAR and AMPAR -mediated glutamatergic transmission, synaptic plasticity and neurogenesis, as well as depressive-like behaviors. It's important for illuminating the mechanisms of depression and exploring new therapeutic targets.