School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, PR China.
Southern Medical University, Nanfang Hospital, Department of Laboratory Medicine, Guangzhou, 510515, Guangdong, PR China.
Neuropharmacology. 2025 Jan 1;262:110206. doi: 10.1016/j.neuropharm.2024.110206. Epub 2024 Nov 1.
Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signaling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signaling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.
Sterile Alpha and TIR Motif Containing 1 (SARM1) 是涉及各种神经过程的蛋白质；然而，其在抑郁症中的作用仍未得到探索。本研究调查了 SARM1 在慢性应激诱导的抑郁症模型和 SARM1 敲除 (KO) 小鼠中对抑郁样行为的贡献。使用一系列行为测试评估抑郁样行为，包括旷场测试 (OFT)、强迫游泳测试 (FST)、蔗糖偏好测试 (SPT) 和悬尾测试 (TST)。使用 ELISA 和 Western blot 技术评估线粒体能量代谢改变、细胞因子水平变化和其他相关分子信号蛋白表达，以研究潜在机制。行为评估 (OFT、FST、SPT、TST) 显示 SARM1 KO 小鼠出现抑郁样表型，伴随着皮质中线粒体能量代谢 (NAD+、ATP) 的改变。有趣的是，SARM1 耗竭导致外周炎症，表现为血浆细胞因子水平升高，但脑区 (皮质) 细胞因子水平没有升高。此外，我们发现 SARM1 KO 小鼠皮质中能量代谢、AMPK 信号和突触可塑性失调。值得注意的是，AMPK 激活剂 AICAR (Acadesine) 改善了抑郁样行为和突触功能障碍，而 AMPK 抑制剂 Compound C 逆转了这些作用。此外，eEF2 激酶抑制剂 NH125 改善了 SARM1 KO 小鼠的抑郁样行为。这些发现表明，SARM1 通过 AMPKα/p-eEF2 信号通路在调节抑郁样行为中起关键作用。靶向 AMPK 信号和突触功能可能为抑郁症提供新的治疗途径。
