Liu Lian, Dai Luqi, Xu Dan, Wang Yinchan, Bai Lin, Chen Xiaoting, Li Mengzhou, Yang Shuai, Tang Yuying
Department of Anesthesiology, West China Second University Hospital, Sichuan University, and Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China; Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, and Department of Respiratory Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610093, China.
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, and Department of Respiratory Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610093, China.
Brain Behav Immun. 2022 Aug;104:139-154. doi: 10.1016/j.bbi.2022.05.014. Epub 2022 May 27.
Dysfunction of glutamatergic synaptic plasticity in basolateral amygdala (BLA) constitutes a critical pathogenic mechanism underlying the depression-like behaviors induced by chronic pain. Astrocytes serve as an important supporting cell modulating glutamatergic synaptic transmission. Here, we found that peripheral spared nerve injury (SNI) induced astrocyte activation to release IL-6 in BLA. Inhibition of astrocyte activity attenuated SNI-induced IL-6 overexpression and depression-like behaviors. Moreover, SNI enhanced the abundance of DHHC2 in synaptosome and DHHC3 in Golgi apparatus, promoted PSD-95 palmitoylation, and increased the recruitment of GluR1 and NR2B at synapses. Suppression of IL-6 or PSD-95 palmitoylation attenuated the synaptic accumulation of GluR1 and NR2B in BLA and improved depression-like behaviors induced by SNI. Furthermore, IL-6 downstream PI3K increased the expression of DHHC3 in Golgi apparatus and facilitated the interaction of palmitoylated PSD-95 with GluR1 and NR2B at synapses. These findings collectively suggested that SNI activated astrocyte to release IL-6 in BLA, which promoted PSD-95 palmitoylation and enhanced the synaptic trafficking of GluR1 and NR2B, and subsequently mediated the depression-like behaviors induced by nerve injury.
基底外侧杏仁核（BLA）中谷氨酸能突触可塑性功能障碍是慢性疼痛诱发抑郁样行为的关键致病机制。星形胶质细胞作为调节谷氨酸能突触传递的重要支持细胞。在此，我们发现外周 spared 神经损伤（SNI）诱导星形胶质细胞激活，使其在 BLA 中释放白细胞介素-6（IL-6）。抑制星形胶质细胞活性可减轻 SNI 诱导的 IL-6 过表达及抑郁样行为。此外，SNI 增强了突触体中 DHHC2 和高尔基体中 DHHC3 的丰度，促进了 PSD-95 的棕榈酰化，并增加了突触处 GluR1 和 NR2B 的募集。抑制 IL-6 或 PSD-95 棕榈酰化可减轻 BLA 中 GluR1 和 NR2B 的突触积累，并改善 SNI 诱导的抑郁样行为。此外，IL-6 下游的磷脂酰肌醇-3-激酶（PI3K）增加了高尔基体中 DHHC3 的表达，并促进了棕榈酰化的 PSD-95 与突触处 GluR1 和 NR2B 的相互作用。这些研究结果共同表明，SNI 激活星形胶质细胞使其在 BLA 中释放 IL-6，后者促进 PSD-95 棕榈酰化并增强 GluR1 和 NR2B 的突触转运，随后介导神经损伤诱导的抑郁样行为。
