Department for Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstr. 5, 79104, Freiburg, Germany; Department Biomedical Sciences of Cells & Systems, Section Molecular Neurology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.
Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9713 RB, Groningen, The Netherlands.
J Affect Disord. 2021 Jan 15;279:501-509. doi: 10.1016/j.jad.2020.10.040. Epub 2020 Oct 26.
Understanding the neurobiology of depression and the mechanism of action of therapeutic measures is currently a research priority. We have shown that the expression of the synaptic protein Homer1a correlates with depression-like behavior and its induction is a common mechanism of action of different antidepressant treatments. However, the mechanism of Homer1a regulation is still unknown.
We combined the chronic despair mouse model (CDM) of chronic depression with different antidepressant treatments. Depression-like behavior was characterized by forced swim and tail suspension tests, and via automatic measurement of sucrose preference in IntelliCage. The Homer1 mRNA expression and promoter DNA methylation were analyzed in cortex and peripheral blood by qRT-PCR and pyrosequencing.
CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples, while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex. The quantitative analyses of the methylation of 7 CpG sites, located on the Homer1 promoter region containing several CRE binding sites, show a significant increase in DNA methylation in the cortex of CDM mice. In contrast, antidepressant treatments reduce the methylation level.
Homer1 expression and promotor methylation were not analyzed in different blood cell types. Other CpG sites of Homer1 promoter should be investigated in future studies. Our experimental approach does not distinguish between methylation and hydroxymethylation.
We demonstrate that stress-induced depression-like behavior and antidepressant treatments are associated with epigenetic alterations of Homer1 promoter, providing new insights into the mechanism of antidepressant treatment.
了解抑郁症的神经生物学和治疗措施的作用机制是当前的研究重点。我们已经表明，突触蛋白 Homer1a 的表达与抑郁样行为相关，其诱导是不同抗抑郁治疗的共同作用机制。然而，Homer1a 调节的机制尚不清楚。
我们将慢性绝望小鼠模型（CDM）与不同的抗抑郁治疗相结合。通过强迫游泳和悬尾试验以及 IntelliCage 自动测量蔗糖偏好来表征抑郁样行为。通过 qRT-PCR 和焦磷酸测序分析皮质和外周血中的 Homer1 mRNA 表达和启动子 DNA 甲基化。
CDM 小鼠的皮质和血液样本中 Homer1a 和 Homer1b/c mRNA 表达降低，而丙咪嗪和氟西汀的慢性治疗或急性氯胺酮应用仅增加其在皮质中的水平。位于包含多个 CRE 结合位点的 Homer1 启动子区域的 7 个 CpG 位点的甲基化定量分析显示，CDM 小鼠皮质中的 DNA 甲基化水平显著增加。相比之下，抗抑郁治疗可降低甲基化水平。
在不同的血细胞类型中未分析 Homer1 表达和启动子甲基化。在未来的研究中应研究 Homer1 启动子的其他 CpG 位点。我们的实验方法无法区分甲基化和羟甲基化。
我们证明应激诱导的抑郁样行为和抗抑郁治疗与 Homer1 启动子的表观遗传改变有关，为抗抑郁治疗的机制提供了新的见解。
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