DNMT1 通过抑制中枢杏仁核 GABA 能神经元的激活来介导慢性痛相关抑郁。

DNMT1 Mediates Chronic Pain-Related Depression by Inhibiting GABAergic Neuronal Activation in the Central Amygdala.

机构信息

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.

Jiangsu Province Key Laboratory of Anesthesiology, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China.

出版信息

Biol Psychiatry. 2023 Oct 15;94(8):672-684. doi: 10.1016/j.biopsych.2023.03.015. Epub 2023 Mar 29.

DOI:10.1016/j.biopsych.2023.03.015

PMID:37001844

Abstract

BACKGROUND

Chronic pain can induce depressive emotion. DNA methyltransferases (DNMTs) have been shown to be involved in the development of chronic pain and depression. However, the role and mechanism of DNMTs in chronic pain-induced depression are not well understood.

METHODS

In well-established spared nerve injury (SNI)-induced chronic pain-related depression models, the expression of DNMTs and the functional roles and underlying mechanisms of DNMT1 in central amygdala (CeA) GABAergic (gamma-aminobutyric acidergic) neurons were investigated using molecular, pharmacological, electrophysiological, optogenetic, and chemogenetic techniques and behavioral tests.

RESULTS

DNMT1, but not DNMT3a or DNMT3b, was upregulated in the CeA of rats with SNI-induced chronic pain-depression. Inhibition of DNMT1 by 5-Aza or viral knockdown of DNMT1 in GABAergic neurons in the CeA effectively ameliorated the depression-like behaviors induced by chronic pain. The DNMT1 action was associated with methylation at the CpG-rich Gad1 promoter and GAD67 downregulation, leading to a decrease of GABAergic neuronal activity. Optogenetic activation of GABAergic neurons in the CeA improved SNI-induced depression-like behaviors. Moreover, optogenetic or chemogenetic inhibition of GABAergic neurons in the CeA reversed DNMT1 knockdown-induced improvement of depression-like behaviors in SNI mice.

CONCLUSIONS

Our findings suggest that DNMT1 is involved in the development of chronic pain-related depression by epigenetic repression of GAD67, leading to the inhibition of GABAergic neuronal activation. This study indicates that DNMT1 could be a potential target for the treatment of chronic pain-related depression.

摘要

背景

慢性疼痛可诱发抑郁情绪。DNA 甲基转移酶（DNMTs）已被证明参与了慢性疼痛和抑郁的发展。然而，DNMTs 在慢性痛诱导性抑郁中的作用和机制尚不清楚。

方法

在建立完善的 spared nerve injury（SNI）诱导的慢性疼痛相关抑郁模型中，使用分子、药理学、电生理学、光遗传学和化学遗传学技术以及行为测试，研究了中央杏仁核（CeA）GABA 能（γ-氨基丁酸能）神经元中 DNMTs 的表达以及 DNMT1 的功能作用和潜在机制。

结果

在 SNI 诱导的慢性痛-抑郁大鼠的 CeA 中，DNMT1 而不是 DNMT3a 或 DNMT3b 上调。DNMT1 在 CeA 中 GABA 能神经元的抑制作用通过 5-Aza 或病毒敲低有效改善了慢性疼痛诱导的抑郁样行为。DNMT1 作用与 Gad1 启动子的 CpG 富含区的甲基化和 GAD67 的下调有关，导致 GABA 能神经元活性降低。CeA 中 GABA 能神经元的光遗传学激活改善了 SNI 诱导的抑郁样行为。此外，CeA 中 GABA 能神经元的光遗传学或化学遗传学抑制逆转了 SNI 小鼠中 DNMT1 敲低诱导的抑郁样行为的改善。