反复给予 D-麦角酸二乙酰胺（LSD）对前额叶皮层 DNA 甲基化和蛋白质表达的调制：对神经营养、神经营养和神经可塑性信号的影响。

Modulation of DNA methylation and protein expression in the prefrontal cortex by repeated administration of D-lysergic acid diethylamide (LSD): Impact on neurotropic, neurotrophic, and neuroplasticity signaling.

机构信息

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada.

Department of Oncology, McGill University, Montreal, QC, Canada; HKG Epitherapeutics, Hong Kong.

出版信息

Prog Neuropsychopharmacol Biol Psychiatry. 2022 Dec 20;119:110594. doi: 10.1016/j.pnpbp.2022.110594. Epub 2022 Jun 28.

DOI:10.1016/j.pnpbp.2022.110594

PMID:35777526

Abstract

AIM

Psychedelic compounds elicit relief from mental disorders. However, the underpinnings of therapeutic improvement remain poorly understood. Here, we investigated the effects of repeated lysergic acid diethylamide (LSD) on whole-genome DNA methylation and protein expression in the mouse prefrontal cortex (PFC).

METHODS

Whole genome bisulphite sequencing (WGBS) and proteomics profiling of the mouse prefrontal cortex (PFC) were performed to assess DNA methylation and protein expression changes following 7 days of repeated LSD administration (30 μg/kg/day); a treatment we previously found to potentiate excitatory neurotransmission and to increase dendritic spine density in the PFC in mice. qRT-PCR was employed to validate candidate genes detected in both analyses.

RESULTS

LSD significantly modulated DNA methylation in 635 CpG sites of the mouse PFC, and in an independent cohort the expression level of 178 proteins. Gene signaling pathways affected are involved in nervous system development, axon guidance, synaptic plasticity, quantity and cell viability of neurons and protein translation. Four genes and their protein product were detected as differentially methylated and expressed, and their transcription was increased. Specifically, Coronin 7 (Coro7), an axon guidance cue; Penta-EF-Hand Domain Containing 1 (Pef1), an mTORC1 and cell cycle modulator; Ribosomal Protein S24 (Rps24), required for pre-rRNA maturation and biogenesis of proteins involved with cell proliferation and migration, and Abhydrolase Domain Containing 6, Acylglycerol Lipase (Abhd6), a post-synaptic lipase.

CONCLUSIONS

LSD affects DNA methylation, altering gene expression and protein expression related to neurotropic-, neurotrophic- and neuroplasticity signaling. This could represent a core mechanism mediating the effects of psychedelics.

摘要

目的

迷幻化合物可缓解精神障碍。然而，治疗效果改善的基础仍知之甚少。在此，我们研究了重复给予麦角酸二乙酰胺（LSD）对小鼠前额叶皮质（PFC）全基因组 DNA 甲基化和蛋白质表达的影响。

方法

采用全基因组亚硫酸氢盐测序（WGBS）和蛋白质组学分析方法，评估重复给予 LSD（30μg/kg/天）后 7 天对小鼠 PFC 的 DNA 甲基化和蛋白质表达变化；我们之前发现该治疗方法可增强 PFC 中的兴奋性神经传递，并增加树突棘密度。采用 qRT-PCR 验证两种分析中检测到的候选基因。

结果

LSD 显著调节了小鼠 PFC 中 635 个 CpG 位点的 DNA 甲基化，在独立队列中还调节了 178 种蛋白质的表达水平。受影响的基因信号通路涉及神经系统发育、轴突导向、突触可塑性、神经元数量和细胞活力以及蛋白质翻译。检测到 4 个基因及其蛋白产物存在差异甲基化和表达，其转录增加。具体而言，轴突导向因子 Coronin 7（Coro7）；mTORC1 和细胞周期调节剂 Penta-EF-Hand Domain Containing 1（Pef1）；核糖体蛋白 S24（Rps24），对 pre-rRNA 成熟和参与细胞增殖和迁移的蛋白质生物发生至关重要，以及酰基甘油脂肪酶的突触后脂酶 Abhydrolase Domain Containing 6，Acylglycerol Lipase（Abhd6）。