Involvement of CX3CL1/CX3CR1 in depression and cognitive impairment induced by chronic unpredictable stress and relevant underlying mechanism
Involvement of CX3CL1/CX3CR1 in depression and cognitive impairment induced by chronic unpredictable stress and relevant underlying mechanism
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CX3CL1/CX3CR1参与慢性不可预测应激诱发的抑郁和认知障碍及其机制
DOI：
10.1016/j.bbr.2019.112371
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发表时间：
2020-03-02
影响因子：
2.7
通讯作者：
Zhang, Chao
中科院分区：
文献类型：
--
作者：
Liu, Ye;Zhang, Tianxiang;Zhang, Chao
研究表明，神经炎症加剧有助于抑郁症的发病机制。神经炎症的主要参与者是小胶质细胞，据报道，fractalkine信号传导（包括主要由神经元表达的趋化因子CX 3CL 1及其受体CX 3CR 1，几乎只存在于健康大脑中的小胶质细胞上）对小胶质细胞的活性有重要的调节作用。本研究的目的是探讨CX 3CR 1缺陷是否与慢性不可预测性应激（CUS）后的不同结局相关及其可能机制。对野生型（WT）和CX 3CR 1缺陷型（CX 3CR 1（-/-））小鼠进行CUS 3周。CX 3CR 1（-/-）小鼠在蔗糖偏好实验、旷场实验和强迫游泳实验中表现出更好的表现，证明CX 3CR 1缺陷可减轻抑郁样障碍，如快感缺失、焦虑或绝望。然而，从Morris水迷宫和新物体识别的结果来看，CX 3CR 1（-/-）小鼠也表现出较轻的认知障碍。记录长时程增强以检测突触可塑性，其结果与认知能力测试结果一致。真实的时间PCR和免疫荧光染色结果均表明，CX 3 CR 1缺陷促进了小胶质细胞的交替激活，从而减少了炎症细胞因子的释放，这一点得到了ELISA和流式细胞术的证实。可能由于减轻了神经炎症，CX 3CR 1缺陷型小鼠比WT组表现出更高的恢复力，以对抗由LPS诱导的血脑屏障通透性过高和树突棘丢失（如Golgi和DiI染色所示）。上述结果表明，通过CX 3CR 1-CX 3CL 1通路阻断神经元-小胶质细胞的通讯可减弱CUS对抑郁样障碍和认知障碍的影响。
Studies have suggested that heightened neuroinflammation contributes to the pathogenesis of depressive disorder. A major participant in neuroinflammation is microglia, and fractalkine signaling (which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in healthy brains) has been reported to critically regulate microglial activity. The aim of this study was to investigate whether CX3CR1 deficiency was associated with a different outcome following chronic unpredictable stress (CUS) and the possible mechanism. Wild-type (WT) and CX3CR1-deficient (CX3CR1(-/-)) mice were subjected to CUS for 3 weeks. CX3CR1(-/-) mice displayed a better performance through sucrose preference test, open field test and forced swim test, which demonstrated that CX3CR1 deficiency alleviated depressive-like disturbances, such as anhedonia, anxiety or hopelessness. Nevertheless, CX3CR1(-/-) mice also showed less severe cognitive impairment from the results of Morris Water Maze and Novel object recognition. Long-term potentiation was recorded to test the synaptic plasticity and its result was consistent with that of cognitive ability tests. Both results of real time-PCR and immunofluorescence staining demonstrated that CX3CR1 deficiency facilitated the alternative activation of microglia, thus attenuated the release of inflammatory cytokines, which was verified by ELISA and flow cytometry. Maybe due to the mitigated neuroinflammation, CX3CR1-deficient mice showed higher resilience to CUS-induced blood brain barrier hyperpermeability and loss of dendrite spine (as showed by Golgi and DiI staining) than WT group. All of above results indicated that hampering neuron-microglia communication via CX3CR1-CX3CL1 pathway attenuated the effects of CUS on depressive-like disturbances and cognitive impairment.