Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University, Ningbo, Zhejiang, PR China.
Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
J Neurochem. 2019 Apr;149(1):111-125. doi: 10.1111/jnc.14670. Epub 2019 Mar 5.
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-β and tumour necrosis factor α 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: 10.1111/jnc.14500.
抑郁症是一种高度复杂的全球致残性精神障碍。不幸的是，目前可用的抗抑郁药在很大比例的患者中并不有效。因此，必须在分子水平上探索抑郁症的潜在机制，以发现治疗抑郁症的新候选分子靶点。在环磷酸腺苷反应元件结合蛋白调节转录共激活因子 1（Crtc1）敲除小鼠中观察到行为和分子抑郁样表型；然而，这些表型的潜在机制尚不清楚。本研究使用重组腺相关病毒（AAV）系统改变 Crtc1 基因表达，探讨海马 CREB 调节转录共激活因子 1（CRTC1）在抑郁症中的作用，并探讨其潜在机制。我们发现，腹侧海马齿状回区域的 shRNA 介导的 Crtc1 基因敲低（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 水平下调。我们在研究中应用了脂多糖给药（0.5mg/kg，腹腔注射）诱导的广泛使用的抑郁症模型，并通过尾巴悬挂和强迫游泳试验中不动时间增加和蔗糖偏好试验中蔗糖消耗减少进行了验证。重要的是，AAV-CRTC1 介导的 CRTC1 过表达可防止脂多糖诱导的抑郁样行为、脑源性神经营养因子和 VGF 下调以及促炎细胞因子如白细胞介素 6、白细胞介素 1-β 和肿瘤坏死因子 α 在小鼠中的积累。总之，我们的研究结果表明，CRTC1 是抑郁样行为的关键因素，为寻找神经炎症和神经营养途径治疗抑郁障碍的新药物靶点提供了重要参考。本期封面图片说明：doi: 10.1111/jnc.14500.
