Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats

• Published in: Experimental & molecular medicine 2018, 50(0), , pp.1-14
• Main Authors: Wan, Yun-Qiang, Feng, Jian-Guo, Li, Mao, Wang, Mao-Zhou, Liu, Li, Liu, Xueru, Duan, Xiao-Xia, Zhang, Chun-Xiang, Wang, Xiao-Bin
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 3' Untranslated Regions; 38; 38/61; 42/109; 631/378/2649; 692/699/476; Animals; Antidepressants; Antidepressive Agents - pharmacology; Apoptosis; Apoptosis - genetics; Biomedicine; Calcium - metabolism; Calcium influx; Cell culture; Cell membranes; Cell survival; Cell Survival - genetics; Disease Models, Animal; Gene Expression; Gene Expression Regulation - drug effects; Gene Silencing; Glutamic Acid - metabolism; Glutamic acid receptors (metabotropic); Ketamine; Ketamine - pharmacology; Male; Medical Biochemistry; Mental depression; Mental disorders; MicroRNAs; MicroRNAs - genetics; miRNA; Molecular Medicine; Molecular modelling; Neuromodulation; Neurons - drug effects; Neurons - metabolism; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiopathology; Rats; Recombination; RNA Interference; Rodents; Signal transduction; Stem Cells; Stress, Psychological; Sucrose; Therapeutic applications; Therapeutic targets; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0164-4

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 Ca 2+ 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. Ketamine: Insights into antidepressant effects Changes in the levels of a microRNA molecule that regulates the activity of a specific gene may be responsible for some of the antidepressant effects of the drug ketamine. Ketamine is used as a tranquilizer and anesthetic, especially in veterinary practice, but there is increasing interest in its antidepressant action in humans. Researchers in China and USA led by Xiao-Bin Wang at the Affiliated Hospital of Southwest Medical University in Luzhou, China, found that ketamine dramatically raised the level