Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors
Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors
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Interleukin-18 缺陷小鼠出现与可能的抑郁样行为相关的海马异常
DOI：
10.1016/j.neuroscience.2019.04.003
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发表时间：
2019
期刊：
影响因子：
3.3
通讯作者：
Matsuyama Tomohiro,
中科院分区：
文献类型：
--
作者：
Yamanishi Kyosuke;Doe Nobutaka;Mukai Keiichiro;Ikubo Kaoru;Hashimoto Takuya;Uwa Noriko;Sumida Miho;El-Darawish Yosif;Gamachi Naomi;Li Wen;Kuwahara-Otani Sachi;Maeda Seishi;Watanabe Yuko;Hayakawa Tetsu;Yamanishi Hiromichi;Matsuyama Tomohiro,
白介素 18 (IL-18) 是一种与重度抑郁症 (MDD) 相关的炎症细胞因子。 MDD 与糖尿病（DM）和肥胖等代谢性疾病密切相关。此外，DM与认知障碍有关，并通过激活促凋亡因子和抑制抗凋亡因子促进海马细胞凋亡。 IL-18 缺陷 (Il18−/−) 小鼠肥胖并患有糖尿病。因此，我们假设IL-18与海马细胞死亡之间存在密切关系，影响与MDD等行为变化相关的神经发生。在C57Bl/6背景下生成Il18−/−雄性小鼠，并使用Il18+/+小鼠作为对照。检查了行为、组织病理学和分子反应，以及对脑内重组 IL-18 给药的反应。与Il18+/+小鼠相比，Il18−/−小鼠学习记忆能力受损，学习动机较低。在Il18-/-小鼠中，在分子层、多态层的突触末端以及齿状回的苔藓纤维中检测到退化的线粒体，表明线粒体异常。由于齿状回线粒体变性，促凋亡分子上调，抗凋亡因子减少，凋亡诱导剂未被裂解，表明细胞凋亡受到抑制。此外，Il18-/-小鼠中齿状回的神经发生和神经元细胞的成熟度降低，而脑内施用重组IL-18促进神经发生的显着恢复。我们的研究结果表明，IL-18 对于线粒体稳态、维持退行性神经细胞的清除以及支持神经发生、正常神经元成熟和海马功能是不可或缺的。
Interleukin-18 (IL-18) is an inflammatory cytokine linked to major depressive disorder (MDD). MDD is closely related to metabolic disorders, such as diabetes mellitus (DM) and obesity. Moreover, DM is associated with cognitive impairment and promotes apoptosis of hippocampal cells by activating pro-apoptotic and inhibiting anti-apoptotic factors. IL-18-deficient (Il18−/−) mice are obese and have DM. Therefore, we hypothesized a close relationship between IL-18 and death of hippocampal cells, affecting neurogenesis related to behavioral changes such as MDD.Il18−/−male mice were generated on the C57Bl/6 background andIl18+/+mice were used as controls. Behavioral, histopathological, and molecular responses, as well as responses to intracerebral recombinant IL-18 administration, were examined. Compared withIl18+/+mice,Il18−/−mice had impaired learning and memory and exhibited lower motivation. In theIl18−/−mice, degenerated mitochondria were detected in synaptic terminals in the molecular layer, the polymorphic layer, and in mossy fibers in the dentate gyrus, suggesting mitochondrial abnormalities. Because of the degeneration of mitochondria in the dentate gyrus, in which pro-apoptotic molecules were upregulated and anti-apoptotic factors were decreased, apoptosis inducers were not cleaved, indicating inhibition of apoptosis. In addition, neurogenesis in the dentate gyrus and the maturity of neuronal cells were decreased in theIl18−/−mice, while intracerebral administration of recombinant IL-18 promoted significant recovery of neurogenesis. Our findings suggested that IL-18 was indispensable for mitochondrial homeostasis, sustaining clearance of degenerative neural cells, and supporting neurogenesis, normal neuronal maturation and hippocampal function.