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

Saiqi Ni; Hua Huang; Danni He; Hang Chen; Chuang Wang; Xin Zhao; Xiaowei Chen; Wei Cui; Wenhua Zhou; Junfang Zhang

doi:10.1111/jnc.14670

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

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

Authors

Saiqi Ni^{1

2

3}, Hua Huang^{1

2

3}, Danni He^{1

2

3}, Hang Chen^{1

2

3}, Chuang Wang^{1

2

3}, Xin Zhao^{1

2

3}, Xiaowei Chen^{1

2

3}, Wei Cui^{1

2

3}, Wenhua Zhou^{1

2

3}, Junfang Zhang^{1

2

3}

Affiliations

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.

PMID: 30697736
DOI: 10.1111/jnc.14670

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dentate Gyrus / metabolism*
Dependovirus
Depression / chemically induced
Depression / metabolism*
Gene Knockdown Techniques
Genetic Vectors
Lipopolysaccharides / toxicity
Male
Mice
Mice, Inbred ICR
Transcription Factors / metabolism*

Substances

Crtc1 protein, mouse
Lipopolysaccharides
Transcription Factors

Associated data

GENBANK/NM_001004062