Zhu Peilin, Luo Yanmin, Li Yue, Tang Jing, Liu Li, Deng Yuhui, Li Jing, Jiang Lin, Yang Wenyu, Xiao Qian, Wang Shun, Zhou Yuning, Chao Fenglei, Zhang Lei, Zhou Chunni, Tang Yong, Liang Xin
Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing, P. R. China.
Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing, P. R. China.
Transl Psychiatry. 2025 Aug 12;15(1):277. doi: 10.1038/s41398-025-03495-0.
Previous studies have indicated that impaired synaptic plasticity is a main pathological alteration in depression. However, the mechanism underlying this pathological change has not been clarified. Adiponectin, an adipokine, crosses the blood‒brain barrier to function in specific brain regions. Previous studies have suggested that the downregulation of adiponectin signaling is involved in the occurrence of depression. The adiponectin receptors (AdipoRs) AdipoR1 and AdipoR2, which serve as the main receptors for adiponectin in the central nervous system, mediate the downstream biological effects of this compound, which has been reported to have positive effects on synaptic plasticity. However, it is not clear whether alterations in adiponectin/AdipoR signaling are associated with impaired synaptic plasticity in depression. Therefore, the aim of this study was to investigate whether changes in the adiponectin/AdipoR pathway in the hippocampus during depression are involved in the regulation of synaptic plasticity damage. We detected reduced plasma concentrations of adiponectin and lower expression levels of AdipoR1 but not AdipoR2 in the hippocampi of mice exposed to chronic unpredictable stress. An adeno-associated virus was subsequently used to knockdown hippocampal AdipoR1 to further verify the effects of decreased expression levels of this receptor on depressive-like behaviors and hippocampal synaptic plasticity. We found that the mice in which hippocampal AdipoR1 was knocked down presented with anhedonia and passive stress-coping behaviors as well as a decreased number of dendritic spines and density of excitatory and inhibitory synapses. Our results suggest that the downregulation of AdipoR1 expression might be an important factor that causes impaired synaptic plasticity in depression. These results may provide new insights into the pathogenesis of depression and new therapeutic targets for treating this disease.
先前的研究表明，突触可塑性受损是抑郁症的主要病理改变。然而，这种病理变化背后的机制尚未阐明。脂联素是一种脂肪因子，可穿过血脑屏障在特定脑区发挥作用。先前的研究表明，脂联素信号下调与抑郁症的发生有关。脂联素受体（AdipoRs）AdipoR1和AdipoR2是中枢神经系统中脂联素的主要受体，介导该化合物的下游生物学效应，据报道该化合物对突触可塑性有积极作用。然而，尚不清楚脂联素/AdipoR信号的改变是否与抑郁症中突触可塑性受损有关。因此，本研究的目的是调查抑郁症期间海马体中脂联素/AdipoR通路的变化是否参与突触可塑性损伤的调节。我们检测到暴露于慢性不可预测应激的小鼠血浆中脂联素浓度降低，海马体中AdipoR1的表达水平降低，但AdipoR2未降低。随后使用腺相关病毒敲低海马体中的AdipoR1，以进一步验证该受体表达水平降低对抑郁样行为和海马体突触可塑性的影响。我们发现，海马体AdipoR1被敲低的小鼠出现快感缺失和被动应激应对行为，以及树突棘数量减少和兴奋性及抑制性突触密度降低。我们的结果表明，AdipoR1表达下调可能是导致抑郁症中突触可塑性受损的重要因素。这些结果可能为抑郁症的发病机制提供新的见解，并为治疗该疾病提供新的治疗靶点。
