Premium
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
Author(s) -
Ni Saiqi,
Huang Hua,
He Danni,
Chen Hang,
Wang Chuang,
Zhao Xin,
Chen Xiaowei,
Cui Wei,
Zhou Wenhua,
Zhang Junfang
Publication year - 2019
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14670
Subject(s) - dentate gyrus , creb , neurotrophic factors , hippocampal formation , coactivator , endocrinology , medicine , neuroscience , biology , transcription factor , receptor , genetics , gene
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 ( CRTC 1) in depression using a recombinant adeno‐associated virus ( AAV ) system to alter Crtc1 gene expression and explore its potential mechanism. We found that sh RNA ‐mediated Crtc1 gene knockdown ( AAV ‐sh CRTC 1) 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, CRTC 1 over‐expression mediated by AAV ‐ CRTC 1 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 CRTC 1 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 .