Microglial stimulation triggered by intranasal lipopolysaccharide administration produces antidepressant-like effect through ERK1/ 2-mediated BDNF synthesis in the hippocampus
Microglial stimulation triggered by intranasal lipopolysaccharide administration produces antidepressant-like effect through ERK1/ 2-mediated BDNF synthesis in the hippocampus
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DOI：
10.1016/j.neuropharm.2023.109693
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发表时间：
2023-09-07
影响因子：
4.7
通讯作者：
Yuan，Xiaomei
中科院分区：
文献类型：
--
作者：
Ni，Mingxie;Zheng，Meng;Yuan，Xiaomei
我们最近报道，通过腹膜内注射低剂量的脂多糖（LPS）来逆转海马齿状回（DG）中小胶质细胞的慢性应激诱导的衰退，改善了慢性应激小鼠的抑郁样行为。在这项研究中，我们发现，单次鼻内给予脂多糖剂量依赖性地改善了慢性不可预测应激（CUS）治疗小鼠的抑郁样行为，悬尾试验（TST）和强迫游泳试验（FST）中不动时间的减少以及蔗糖偏好试验（SPT）中蔗糖摄取的增加证明了这一点。通过输注抗 BDNF 抗体、敲入突变 BDNF Val68Met 等位基因或通过 BDNF 受体拮抗剂 K252a 抑制脑源性神经营养因子 (BDNF) 信号传导，可以消除鼻内施用 LPS 的抗抑郁作用。此外，发现鼻内给予 LPS 可以通过促进 BDNF 合成，以 BDNF 依赖的方式发挥抗抑郁作用，该合成是由细胞外信号调节激酶 1/2 (ERK1/2) 信号介导的，而不是 DG 中蛋白激酶 B (Akt)-哺乳动物雷帕霉素靶点 (mTOR) 信号传导介导的。通过米诺环素抑制小胶质细胞或通过 PLX3397 消耗小胶质细胞能够消除鼻内 LPS 给药对 CUS 诱导的抑郁样行为以及 CUS 诱导的 DG 中磷酸 ERK1/2 和 BDNF 蛋白水平降低的逆转作用。这些结果表明，通过鼻内LPS刺激海马小胶质细胞可以通过ERK1/2依赖的BDNF蛋白合成诱导抗抑郁作用，为开发治疗抑郁症的新策略带来希望。
We recently reported that reversing the chronic stress-induced decline of microglia in the dentate gyrus (DG) of the hippocampus by intraperitoneal injection of a low dose of lipopolysaccharide (LPS) ameliorated depression-like behavior in chronically stressed mice. In this study, we found that a single intranasal administration of LPS dose-dependently improved depression-like behavior in mice treated with chronic unpredictable stress (CUS), as evidenced by the reduction of immobility time in the tail suspension test (TST) and forced swimming test (FST) and by the increase of sucrose uptake in the sucrose preference test (SPT). The antidepressant effects of intranasal administration of LPS could be abolished by inhibition of brain-derived neurotrophic factor (BDNF) signaling by infusion of an anti-BDNF antibody, by knock-in of the mutant BDNF Val68Met allele, or by the BDNF receptor antagonist K252a. In addition, intranasal administration of LPS was found to exert antidepressant effects in a BDNF-dependent manner via promotion of BDNF synthesis mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling in DG. Inhibition of microglia by minocycline or depletion of microglia by PLX3397 was able to abolish the reversal effect of intranasal LPS administration on CUS-induced depression-like behaviors as well as the CUS-induced decrease in phospho-ERK1/2 and BDNF protein levels in DG. These results demonstrate that stimulation of hippocampal microglia by intranasal LPS administration can induce antidepressant effects via ERK1/2-dependent synthesis of BDNF protein, providing hope for the development of new strategies for the treatment of depression.