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.
Highlights
Major depression, characterized as anhedonia and low self-esteem, is one of common psychiatric disorders
We aim to reveal molecular profiles underlying the impairments specific for GABAergic neurons, such as GABA synthesis, release and uptake from depression-like mice induced by chronic unpredictable mild stress (CUMS)
The mouse model of major depressive disorder induced by CUMS In order to examine neuron-specific pathophysiology associated with major depressive disorders, we applied C57 Thy1-YFP/GAD1-GFP mice whose GABAergic and glutamatergic neurons were genetically labeled by green fluorescent protein (GFP) and yellow fluorescent protein (YFP), respectively.[32]
Summary
Major depression, characterized as anhedonia and low self-esteem, is one of common psychiatric disorders. In terms of its pathogenesis, chronic stress to the genetically susceptible individuals leads to the dysfunctions of monoamine, brain-derived neurotrophic factor and hypothalamus–pituitary–adrenal axis,[1,2,3,4,5] which induce the neuron atrophy in the brain reward circuits, such as the prefrontal cortex, nucleus accumbens and amygdala, in these depression patients and depression-like animals.[6,7,8,9,10,11,12] These changes may be caused by a process that environmental stress evokes a series of epigenetic mechanism and gene expression.[13,14] As the physiological coordination between the excitatory and inhibitory neurons is critical for the neuron encoding to manage wellorganized cognitions,[15,16] cell-specific pathology caused by molecular processes in major depressive disorder remains to be elucidated.[17,18,19].
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