去泛素化酶USP2调控AMPA受体在抑郁症中的作用及机制研究

The deubiquitinating enzymes play an important role in protein trafficking and degradation, and are closely related with mental disorders, including autism. However, the relationship between USP2, as a deubiquitination enzyme, and depression is unclear. Recent studies have showed that activation of the Kv7 channel can indirectly positively regulate USP2, and the Kv7 channel activator retigabine has antidepressant effect. Preliminary experiment results showed that silencing USP2 induced depressive behaviors, and accompanied by autophagy enhancement and downregulation of AMPA receptor expression; meanwhile, retigabine exerted antidepressant effect through regulating USP2/autophagy/AMPA receptor signaling pathways. These results suggested that USP2 might play an important role in depression. Based on that, we proposed a hypothesis that USP2 may affect AMPA receptors degradation by regulating autophagy, thus mediate depression. Therefore,this study was to clarify the role of USP2 in the depression, explore the regulation of autophagy by USP2, and reveal the mechanism of USP2 affecting the pathogenesis and treatment of depression by regulating autophagy mediated-AMPA receptor degradation from the levels of molecules, cells, and animals. This study would explore the pathogenesis and treatment mechanism of depression from the new perspective of USP2, and provide new ideas for the treatment of depression.

去泛素化酶在蛋白质的转运与降解中具有重要作用，并且与自闭症等精神疾病密切相关。然而，USP2作为一种去泛素化酶，与抑郁症的关系尚不清楚。近年来研究显示，激活Kv7通道可间接地正向调节USP2，而Kv7通道激活剂retigabine具有抗抑郁作用。预实验结果显示，沉默USP2诱发抑郁行为，并伴随着自噬增强以及AMPA受体表达下调；与此同时，retigabine通过调控USP2/自噬/AMPA受体信号通路发挥抗抑郁作用。这些结果表明USP2在抑郁症中起重要作用。据此我们提出假说：USP2可能通过调节自噬，影响AMPA受体的降解，从而调控抑郁症。因此，本课题拟从分子、细胞、动物水平明确USP2在抑郁症中的作用；探讨USP2对自噬的调控机制；揭示USP2通过自噬调控AMPA受体降解影响抑郁症发病和治疗的机制。本研究将从USP2这个新视点探讨抑郁症的发病和治疗机制，为抑郁症的治疗提供新思路。

去泛素化酶在蛋白质的转运与降解中具有重要作用，并且与自闭症等精神疾病密切相关。然而，USP2作为一种去泛素化酶，与抑郁症的关系尚不清楚。本研究从分子、细胞、动物水平，探讨USP2在抑郁症发病及抗抑郁治疗的作用及其机制。我们发现采用基因沉默USP2可导致小鼠抑郁样行为，抗抑郁药文拉法辛能够抑制沉默USP2的致抑郁作用，同时上调USP2表达；使用药理学抑制剂ML364（抑制USP2活性）诱发小鼠抑郁样行为，而文拉法辛亦能够抑制ML364的致抑郁作用；过表达USP2可取消皮质酮诱发的小鼠抑郁样行为，同时能够纠正皮质酮导致的USP2表达降低。沉默USP2或ML364或皮质酮均可导致小鼠海马内IL-1R2明显降低和p-IκBα (Ser32/36)明显升高，此现象均能够被文拉法所取消；过表达USP2可抑制皮质酮引发的小鼠海马内IL-1R2减少和p-IκBα (Ser32/36)增加。此外，沉默USP2可模拟海马神经元损伤抑郁症细胞模型，而文拉法辛可缓解海马神经元损伤，并且恢复USP2水平；ML364亦可模拟海马神经元损伤抑郁症细胞模型，而文拉法辛也可抑制ML364的致海马神经元损伤作用；过表达USP2可明显改善皮质酮引发的海马神经元损伤，同时纠正皮质酮引发的USP2表达降低。另外，沉默USP2或ML364或皮质酮均显著降低海马神经元中IL-1R2表达，这些作用均可被文拉法辛所抑制；过表达USP2亦可显著抑制皮质酮下调IL-1R2表达的作用。这些结果表明，USP2可能通过影响其下游的IL-1R2和NF-κB信号通路调控抑郁症的发病及抗抑郁治疗。因此，本研究从USP2这个新视点探讨了抑郁症的发病和抗抑郁治疗机制，充实并完善抑郁症的病理生理学机制，并且证实USP2有望作为新的药物靶点治疗抑郁症，为临床上治疗抑郁症提供新的思路。