Acetate supplementation produces antidepressant-like effect via enhanced histone acetylation

Background: Abnormal energy metabolism is often documented in the brain of patients and rodents with depression. In metabolic stress, acetate serves as an important source of acetyl coenzyme A (Ac-CoA). However, its exact role and underlying mechanism remain to be investigated.Method: We used chronic social failure stress (CSDS) to induce depression-like phenotype of C57BL/6J mice. The drugs were administered by gavage. We evaluated the depressive symptoms by sucrose preference test, social interaction, tail suspension test and forced swimming test. The dendritic branches and spine density were detected by Golgi staining, mRNA level was analyzed by real-time quantitative RT-PCR, protein expression level was detected by western blot, and the content of Ac-CoA was detected by ELISA kit.Result: The present study found that acetate supplementation significantly improved the depression-like behaviors of mice either in acute forced swimming test (FST) or in CSDS model and that acetate administration enhanced the dendritic branches and spine density of the CA1 pyramidal neurons. Moreover, the down-regulated levels of BDNF and TrkB were rescued in the acetate-treated mice. Of note, chronic acetate treatment obviously lowered the transcription level of HDAC2, HDAC5, HDAC7, HDAC8, increased the transcription level of HAT and P300, and boosted the content of Ac-CoA in the nucleus, which facilitated the acetylation levels of histone H3 and H4.Limitations: The effect of acetate supplementation on other brain regions is not further elucidated.Conclusion: These findings indicate that acetate supplementation can produce antidepressant-like effects by increasing histone acetylation and improving synaptic plasticity in hippocampus.

背景：经常在患者和不同抑郁啮齿动物的大脑中记录异常的能量代谢。在代谢应激中，醋酸盐是乙酰辅酶A（AC-COA）的重要来源。但是，其确切的作用和潜在机制仍有待研究。方法：我们使用慢性社会失败应力（CSD）诱导C57BL/6J小鼠的抑郁样表型。这些药物是通过饲料施用的。我们通过蔗糖偏好测试，社交互动，尾悬架测试和强迫游泳测试评估了抑郁症状。通过高尔基染色检测到树突状分支和脊柱密度，通过实时定量RT-PCR分析mRNA水平，通过蛋白质印迹检测到蛋白质表达水平，通过蛋白质印迹检测到AC-COA的含量，通过ELISA kit.try.stresult.stresult.stresult：本研究发现，乙酸补充可显着改善了乙酸较大的抑郁症模型或抑郁症的表现。醋酸盐给药增强了CA1锥体神经元的树突分支和脊柱密度。此外，在经过醋酸盐处理的小鼠中救出了BDNF和TRKB的下调水平。值得注意的是，慢性乙酸治疗显然降低了HDAC2，HDAC5，HDAC7，HDAC8的转录水平，提高了HAT和p300的转录水平，并提高了核中AC-COA的含量表明补充乙酸可以通过增加组蛋白乙酰化并改善海马的突触可塑性来产生抗抑郁样作用。