Impaired GABA synthesis, uptake and release are associated with depression-like behaviors induced by chronic mild stress

Abstract

Major depression is a prevalent emotion disorder. Chronic stressful life in genetically susceptible individuals is presumably a major etiology that leads to neuron and synapse atrophy in the limbic system. Molecular mechanisms underlying the pathological changes remain elusive. Mice were treated by chronic unpredictable mild stress (CUMS) until they demonstrated depression-like behavior. GABA release in the medial prefrontal cortex was evaluated by cell electrophysiology and imaging. Molecular profiles related to GABA synthesis and uptake were investigated by the high-throughput sequencings of microRNAs and mRNAs as well as western blot analysis in this cortical area. In CUMS-induced depression mice, there appear the decreases in the innervation and function of GABAergic axons and in the levels of mRNAs and proteins of glutamate decarboxylase-67, vesicular GABA transporter and GABA transporter-3. miRNA-15b-5p, miRNA-144-3p, miRNA-582-5p and miRNA-879-5p that directly downregulate such mRNAs increase in this cortex. Our results suggest that chronic mild stress impairs GABA release and uptake by upregulating miRNAs and downregulating mRNAs and proteins, which may constitute the subcellular and molecular mechanisms for the lowered GABA tone in major depression.

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

“…Memory to these negative events induced by the CUMS drove them to feel cognitive and emotional disability and to fall into anhedonia and low self‐esteem (Wang & Cui, 2017, 2018). The paradigms for the CUMS included social isolation, tilted cage, empty cage, damp sawdust cage, restraint space, white noise, strobe light, and circadian disturbance (Ma, Guo, Xu, Cui, & Wang, 2016; Ma, Xu, et al, 2016; Xu et al, 2016; Zhu et al, 2017). Except for social isolation, such conditions were randomly used to treat mice in separation or combination manner each day (see Table one in Xu et al, 2016 for detail).…”

“…These measurements in each of mice would be considered as significant change if the values of the SPT and YMT reduced above 20% of its self‐control value and the immobile time of the FST increased above 15% of its self‐control value. These standards set up based on the averaged values in previous studies (Ma, Xu, et al, 2016; Xu et al, 2016; Zhu et al, 2017). Mice with significant changes in three tests were called as CUMS‐induced depression‐like mice or depression‐like mice.…”

“…Both sides of the nucleus accumbens (NAc) were quickly isolated and dissected on ice‐cold glass slide. Total RNAs from the NAc in each mouse were isolated by using TRIzol Reagent (Life Technologies, Carlsbad, CA) as described (Ma, Xu, et al, 2016), after which RNA samples in the dry ice were delivered to Beijing Genomics Institute (BGI) in China for high‐throughput sequencing analysis. The concentration of total RNA, the value of RNA integrity number (RIN), and the ratios of 28S to 18S ribosomal RNA were measured by using 2100 Bioanalyzer (Agilent Technology) with RNA 6000 nano Reagents Port 1 for quality control of RNA samples.…”

“…The concentration of total RNA, the value of RNA integrity number (RIN), and the ratios of 28S to 18S ribosomal RNA were measured by using 2100 Bioanalyzer (Agilent Technology) with RNA 6000 nano Reagents Port 1 for quality control of RNA samples. The samples with total RNA amount larger than 10 μg, the concentration larger than 200 ng/μL, the RIN larger than 8, and the ratio of 28S to 18S larger than 1.5 were selected for the construction of transcriptome and small RNA libraries (Ma, Guo, et al, 2016; Ma, Xu, et al, 2016). NAc tissues from three mice of control, CUMS‐MDD, and CUMS‐resilience groups were used for high‐throughput sequencing with correlation coefficient larger than 0.8.…”

“…Pathological changes in monoamine synapses, hypothalamus‐pituitary‐adrenal axis, and brain‐derived neurotrophic factor are believed to cause neuronal atrophy in the ventral tegmental area, nucleus accumbens, and prefrontal cortex from depressive patients and depression‐like animals (Banasr, Dwyer, & Duman, 2011; Bennett et al, 2008; Duman, 2010; Elizalde et al, 2008; Ma, Xu, et al, 2016; Pittenger & Duman, 2008; Sandi & Haller, 2015; Xu, Cui, & Wang, 2016). In addition, major depression may be caused by a lack of reward in life to lower the use in the function of brain reward circuits including the ventral tegmental area, nucleus accumbens, and prefrontal cortex (Wang & Cui, 2015; Zhu, Wang, Ma, Cui, & Wang, 2017).…”