Adeno-associated virus-mediated over-expression of CREB-regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide-induced depression-like behaviour in mice
Adeno-associated virus-mediated over-expression of CREB-regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide-induced depression-like behaviour in mice
复制标题
腺相关病毒介导的海马齿状回 CREB 调节转录共激活因子 1 的过度表达可改善脂多糖诱导的小鼠抑郁样行为
DOI：
10.1111/jnc.14670
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发表时间：
2019-04-01
影响因子：
4.7
通讯作者：
Zhang, Junfang
中科院分区：
文献类型：
--
作者：
Ni, Saiqi;Huang, Hua;Zhang, Junfang
抑郁症是一种高度复杂的全球性致残性精神障碍。不幸的是，目前可用的抗抑郁药对很大比例的患者并不有效。因此，必须在分子水平上探索抑郁症的潜在机制，为抑郁症的治疗寻找新的候选分子靶点。在cAMP反应元件结合蛋白调节的转录辅活化子1(Crtc1)基因敲除小鼠中观察到了行为和分子抑郁样内表型；然而，这些内表型的潜在机制尚不清楚。本工作利用重组腺相关病毒(AAV)系统改变Crtc1基因的表达，研究了海马区CREB调节的转录辅活化子1(CRTc1)在抑郁症中的作用，并探讨其可能的机制。我们发现，在腹侧海马齿状回区域，shRNA介导的Crtc1基因敲除(AAV-shCRTC1)直接导致抑郁样行为和脑源性神经营养因子和神经肽VGF水平的下调。一种广泛应用的内毒素(0.5 mg/kg)诱导的抑郁模型在悬尾和强迫游泳试验中增加了不动时间，在蔗糖偏好试验中减少了蔗糖消耗。重要的是，由AAV-CRTC1介导的CRTC1在腹侧齿状回区域的过度表达阻止了内毒素诱导的小鼠抑郁样行为、脑源性神经营养因子和VGF的下调以及促炎细胞因子如IL-6、IL-1-β和肿瘤坏死因子α的积累。综上所述，我们的发现表明CRTC1是抑郁症行为的关键因素，并为在治疗抑郁症的神经炎性和神经营养通路中寻找新的药物靶点提供了重要的参考。本期封面图片：DOI：。
Depression is a highly complex global disabling psychiatric disorder. Unfortunately, the currently available antidepressants are not effective in a significant percentage of patients. Therefore, the underlying mechanisms of depression must be explored at the molecular level to discover new candidate molecular targets for depression treatment. Behavioural and molecular depression-like endophenotypes have been observed in cyclic AMP response element-binding protein-regulated transcription coactivator 1 (Crtc1) knockout mice; however, the underlying mechanism for these endophenotypes remains unclear. This work investigated the role of hippocampal CREB-regulated transcription coactivator 1 (CRTC1) in depression using a recombinant adeno-associated virus (AAV) system to alter Crtc1 gene expression and explore its potential mechanism. We found that shRNA-mediated Crtc1 gene knockdown (AAV-shCRTC1) in the dentate gyrus regions of the ventral hippocampus directly resulted in depression-like behaviours and down-regulation of brain-derived neurotrophic factor and neuropeptide VGF levels. A widely used depression model induced by lipopolysaccharide administration (0.5 mg/kg, i.p.) was applied in our study and was validated by increased immobility time in the tail-suspension and forced swim tests and decreased sucrose consumption in the sucrose preference test. Importantly, CRTC1 over-expression mediated by AAV-CRTC1 in the ventral dentate gyrus regions prevented lipopolysaccharide-induced depressive-like behaviours, the down-regulation of brain-derived neurotrophic factor and VGF, and the accumulation of pro-inflammatory cytokines such as interleukin-6, interleukin 1-beta and tumour necrosis factor alpha in mice. Together, our findings indicate that CRTC1 is a key factor in depression-like behaviour and provide an important reference for finding a novel drug target in the neuroinflammatory and neurotrophic pathways for curing depressive disorders. Cover Image for this issue: doi: .