Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China.
Laboratory of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China.
Exp Mol Med. 2018 Oct 29;50(10):1-14. 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 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.
氯胺酮具有快速、明显和持久的抗抑郁作用，但其潜在的分子机制尚不清楚。最近，microRNAs（miRNAs）已成为氯胺酮抗抑郁作用的重要调节因子。我们研究了氯胺酮给药和慢性不可预测轻度应激（CUMS）后大鼠大脑中 miR-29b-3p 的变化，并使用蔗糖偏好测试和强迫游泳测试来评估大鼠的抑郁样状态。我们使用重组腺相关病毒（rAAV）或表达 miR-29b-3p 的慢病毒观察代谢型谷氨酸受体 4（GRM4）的变化。细胞培养和电生理记录用于评估 miR-29b-3p 的功能。氯胺酮显著增加了正常大鼠前额叶皮层中的 miR-29b-3p 表达。双荧光素酶报告试验证实 GRM4 是 miR-29b-3p 的靶标。抑郁样大鼠前额叶皮层中的 miR-29b-3p 水平下调，而 GRM4 水平上调。氯胺酮处理增加了抑郁样大鼠和原代神经元前额叶皮层中的 miR-29b-3p 表达并降低了 GRM4 表达。通过过表达和沉默 miR-29b-3p，我们进一步验证了 miR-29b-3p 可以负调控 GRM4。沉默 miR-29b-3p 抑制了前额叶皮层神经元中的 Ca2+内流。miR-29b-3p 的过表达有助于细胞存活、树突生长、细胞外谷氨酸浓度升高和细胞凋亡抑制。rAAV 介导的 miR-29b-3p 过表达导致 CUMS 大鼠抑郁行为明显缓解，GRM4 表达降低。miR-29b-3p/GRM4 通路是氯胺酮在抑郁样大鼠中抗抑郁作用的关键介质，可作为治疗重度抑郁症的潜在治疗靶点。
