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KMID : 0620920180500100140
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Experimental & Molecular Medicine
2018 Volume.50 No. 10 p.140 ~ p.140
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Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats
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Wan Yun-Qiang
Feng Jian-Guo
Li Mao
Wang Mao-Zhou
Liu Li
Liu Xueru
Duan Xiao-Xia
Zhang Chun-Xiang
Wang Xiao-Bin
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Abstract
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Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine’s antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats’ depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine’s antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder.
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KEYWORD
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Cognitive neuroscience, Psychiatric disorders
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