The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression-like behaviours in mice

Abstract

Depression is the most frequent psychiatric disorder in the world. Recent evidence has shown that stress-induced GABAergic dysfunction in the nucleus accumbens (NAc) contributed to the pathophysiology of depression. However, the molecular mechanisms underlying these pathological changes remain unclear. In this study, mice were constantly treated with the chronic unpredictable mild stress (CUMS) till showing depression-like behaviours expression. GABA synthesis, release and uptake in the NAc tissue were assessed by analysing the expression level of genes and proteins of Gad-1, VGAT and GAT-3 by qRT-PCR and Western blotting. The miRNA/mRNA network regulating GABA was constructed based on the bioinformatics prediction software and further validated by dual-luciferase reporter assay in vitro and qRT-PCR in vivo, respectively. Our results showed that the expression level of GAT-3, Gad-1 and VGAT mRNA and protein significantly decreased in the NAc tissue from CUMS-induced depression-like mice than that of control mice. However, miRNA-144-3p, miRNA-879-5p, miR-15b-5p and miRNA-582-5p that directly down-regulated the expression of Gad-1, VGAT and GAT-3 were increased. In the mRNA/miRNA regulatory GABA network, Gad-1 and VGAT were directly regulated by binding seed sequence of miR-144-3p, and miR-15b-5p, miR-879-5p could be served negative post-regulators by binding to the different sites of VGAT 3'-UTR. Chronic stress causes the impaired GABA synthesis, release and uptake by up-regulating miRNAs and down-regulating mRNAs and proteins, which may reveal the molecular mechanisms for the decreased GABA concentrations in the NAc tissue of CUMS-induced depression.

Keywords: GABA; depression; nucleus accumbens; stress.