Autophagy promotes membrane trafficking of NR2B to alleviate depression by inhibiting AQP4 expression in mice
Autophagy promotes membrane trafficking of NR2B to alleviate depression by inhibiting AQP4 expression in mice
复制标题
自噬促进 NR2B 膜运输，通过抑制 AQP4 表达缓解小鼠抑郁症
DOI：
10.1016/j.yexcr.2022.113298
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发表时间：
2022
影响因子：
3.7
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Liu X;Gu XH;Zheng LL;Xu LJ;Yang YJ;Yang G;Wu HJ;Chen ZZ;Wang W
抑郁症是一种高发精神疾病，严重影响人类健康。据报道，AQP4与抑郁症密切相关，但其潜在机制仍不清楚。这项工作旨在研究 AQP4 在抑郁症中的功能作用。通过给予慢性社交挫败应激（CSDS）来构建抑郁小鼠模型。我们发现AQP4在CSDS小鼠的海马组织中高表达。 AQP4 敲低可减轻 CSDS 小鼠的抑郁症并增强 NR2B 和 PSD95 的表达。此外，用N-甲基-d-天冬氨酸（NMDA）处理原代海马神经元以诱导神经元损伤。 AQP4 过表达抑制细胞活力并促进 NMDA 处理的原代海马神经元凋亡。在 NMDA 处理的原代海马神经元中，AQP4 的上调抑制了 NR2B（表面）的表达，并增强了 NR2B（细胞内）、P-NR2B、CaMK II 和 CK2 的表达。 KN-93（CaMK II 抑制剂）或 TBB（CK2 抑制剂）治疗消除了 AQP4 上调所带来的影响。雷帕霉素处理通过激活自噬增强原代海马神经元中 NR2B（表面）的表达，并抑制 AQP4、NR2B（细胞内）和 P-NR2B 的表达。激活的自噬通过抑制 AQP4 表达来缓解 CSDS 小鼠的抑郁症。总之，我们的数据表明，自噬通过抑制小鼠中 AQP4 的表达来改善抑郁症，并且 AQP4 敲低可促进 NR2B 的膜运输并通过 CaMK II/CK2 途径抑制 NR2B 的磷酸化。因此，我们的工作表明 AQP4 可能是抗抑郁药物开发的一个有前途的分子靶点。 • AQP4 敲低可减轻 CSDS 小鼠的抑郁样行为。 • AQP4 敲低可通过 CaMK II/CK2 途径促进 NR2B 膜运输。 • AQP4 敲低可通过 CaMK II/CK2 途径抑制 NR2B 磷酸化。 • 自噬诱导AQP4 降解。 • 自噬通过抑制 CSDS 小鼠中 AQP4 的表达来改善抑郁症。
Depression is a high-incidence mental illness that seriously affects human health. AQP4 has been reported to be closely associated with depression, while the underlying mechanism is still unclear. This work aimed to investigate the functional role of AQP4 in depression. Depression mouse model was constructed by administration of chronic social defeat stress (CSDS). We found that AQP4 was highly expressed in the hippocampal tissues of CSDS mice. AQP4 knockdown alleviated depression and enhanced the expression of NR2B and PSD95 in CSDS mice. Moreover, primary hippocampal neurons were treated with N-methyl- d -aspartate (NMDA) to induce neuron injury. AQP4 overexpression repressed cell viability and promoted apoptosis of NMDA-treated primary hippocampal neurons. AQP4 up-regulation repressed the expression of NR2B (surface), and enhanced the expression of NR2B (intracellular), P-NR2B, CaMK II and CK2 in the NMDA-treated primary hippocampal neurons. The influence conferred by AQP4 up-regulation was abolished by KN-93 (CaMK II inhibitor) or TBB (CK2 inhibitor) treatment. Rapamycin treatment enhanced the expression of NR2B (surface), and repressed the expression of AQP4, NR2B (intracellular) and P-NR2B in the primary hippocampal neurons by activating autophagy. The activated autophagy alleviated depression in CSDS mice by repressing AQP4 expression. In conclusion, our data demonstrated that autophagy ameliorated depression by repressing AQP4 expression in mice, and AQP4 knockdown promoted membrane trafficking of NR2B and inhibited phosphorylation of NR2B via CaMK II/CK2 pathway. Thus, our work suggests that AQP4 may be a promising molecular target for the development of antidepressant drugs. • AQP4 knockdown alleviates depression-like behaviors in CSDS mice. • AQP4 knockdown promotes NR2B membrane trafficking via CaMK II/CK2 pathway. • AQP4 knockdown inhibits NR2B phosphorylation via CaMK II/CK2 pathway. • Autophagy induces degradation of AQP4. • Autophagy improves depression by inhibiting AQP4 expression in CSDS mice.