期刊
JOURNAL OF NEUROCHEMISTRY
卷 149, 期 1, 页码 111-125出版社
WILEY
DOI: 10.1111/jnc.14670
关键词
brain-derived neurotrophic factor; CREB-regulated transcription coactivator 1; depression; lipopolysaccharide; neuroinflammation; VGF
资金
- National Natural Science Foundation of China (NSFC) [81171036, 81371224, 81671089]
- Natural Science Foundation of Zhejiang Province [LY19H090003]
- Natural Science Foundation of Ningbo [2018A610288]
- Ningbo Municipal Innovation Team of Life Science and Health [2015C110026]
- Scientific Research Foundation of Graduate School of Ningbo University [G18122]
- Xinmiao Talents Program of Zhejiang [2018R405051]
- Student Research and Innovation Program (SRIP)
- K.C. Wong Magna Fund in Ningbo University
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: .
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