Age-dependent regulation of depression-like behaviors through modulation of adrenergic receptor α1A subtype expression revealed by the analysis of interleukin-1 receptor antagonist knockout mice
Age-dependent regulation of depression-like behaviors through modulation of adrenergic receptor α1A subtype expression revealed by the analysis of interleukin-1 receptor antagonist knockout mice
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DOI：
10.1016/j.neuroscience.2011.06.031
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发表时间：
2011-09
期刊：
影响因子：
3.3
通讯作者：
C. Wakabayashi;Y. Kiyama;H. Kunugi;T. Manabe;Y. Iwakura
中科院分区：
文献类型：
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作者：
C. Wakabayashi;Y. Kiyama;H. Kunugi;T. Manabe;Y. Iwakura
白介素1(IL-1)在应激反应中起重要作用，其mRNA在应激负荷作用下在大脑中被诱导，然而，IL-1在高级脑功能及其异常中的确切作用尚不清楚。在这里，我们报道了IL-1受体拮抗剂(IL-1ra)基因敲除(KO)小鼠，其缺乏对抗IL-1受体的IL-1ra分子，仅在幼年阶段(8周)在尾部悬挂试验(TST)和强迫游泳试验(FST)中表现出抗抑郁样表型，而在后期(20和32周)表型消失。给予肾上腺素能受体(AR)拮抗剂对抗ARα1、ARα2和ARβ亚型可逆转这些抗抑郁表型。虽然IL-1Ra KO和野生型(WT)仔鼠在海马区或大脑皮层中5-羟色胺(5-HT)、去甲肾上腺素(NE)和多巴胺(DA)的含量没有显著差异，但ARα1A亚型在大脑皮层中的表达水平发生了显著变化。有趣的是，ARα1A亚型的表达变化与IL-1Ra KO小鼠TST和FST的年龄相关性变化相关。此外，在C57BL/6J雄性小鼠身上，温和的束缚应激导致TST和FST中的抗抑郁表型与突变小鼠相似。这些结果表明，基因操作诱导的IL-1信号的持续激活影响ARα1A亚型的表达，IL-1系统对肾上腺素能信号的修饰最终可能导致明显的精神异常，如抑郁症，该突变小鼠可被视为儿童和青少年特有的抑郁症模型动物。
Interleukin-1 (IL-1) plays a crucial role in stress responses and its mRNA is induced in the brain by stress load; however, the precise role of IL-1 in higher brain functions and their abnormalities is largely unknown. Here, we report that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lack IL-1Ra molecules that antagonize the IL-1 receptor, displayed anti-depression-like phenotypes in the tail suspension test (TST) and forced-swim test (FST) only at a young stage (8 weeks), whereas the phenotypes disappeared at later stages (20 and 32 weeks). These anti-depression-like phenotypes were reversed by administration of adrenergic receptor (AR) antagonists against the ARα1, ARα2, and ARβ subtypes. Although the contents of 5-HT, norepinephrine (NE), and dopamine (DA), which are known to be associated with major symptoms of psychiatric disorders, were not significantly different in the hippocampus or cerebral cortex between IL-1Ra KO and their wild-type (WT) littermate mice, the mRNA expression level of the ARα1Asubtype was significantly changed in the cerebral cortex. Interestingly, the change in expression of the ARα1Asubtype was correlated with an age-dependent alteration in the TST and FST in IL-1Ra KO mice. Furthermore, mild immobilization stress loaded on C57BL/6J male mice caused similar anti-depression-like phenotypes in the TST and FST to those observed in mutant mice. These results suggest that sustained activation of IL-1 signaling induced by gene manipulation in mutant mice affects the expression of the ARα1Asubtype and that modification of adrenergic signaling by the IL-1 system may ultimately cause significant psychiatric abnormalities such as depression, and this mutant mouse could be regarded as a model animal of depression that specifically appears in children and adolescents.