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J Neurochem. 2019 Apr;149(1):111-125. doi: 10.1111/jnc.14670. Epub 2019 Mar 5.

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.

Ni S1,2,3, Huang H1,2,3, He D1,2,3, Chen H1,2,3, Wang C1,2,3, Zhao X1,2,3, Chen X1,2,3, Cui W1,2,3, Zhou W1,2,3, Zhang J1,2,3.

Author information

1
Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University, Ningbo, Zhejiang, PR China.
2
Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
3
Ningbo Key Laboratory of Behavioural Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.

Abstract

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.

KEYWORDS:

VGF ; CREB-regulated transcription coactivator 1; brain-derived neurotrophic factor; depression; lipopolysaccharide; neuroinflammation

PMID:
30697736
DOI:
10.1111/jnc.14670

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