Santos Lucas, Behrens Luiza, Barbosa Camila, Tiefensee-Ribeiro Camila, Rosa-Silva Helen, Somensi Nauana, Brum Pedro Ozorio, Silveira Alexandre Kleber, Rodrigues Matheus Scarpatto, de Oliveira Jade, Gelain Daniel Pens, Almeida Roberto F, Moreira José Cláudio Fonseca
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Neurobiol. 2024 Aug;61(8):5718-5737. doi: 10.1007/s12035-024-03912-3. Epub 2024 Jan 16.
Major Depressive Disorder (MDD) is a severe and multifactorial psychiatric condition. Evidence has shown that environmental factors, such as stress, significantly explain MDD pathophysiology. Studies have hypothesized that changes in histone methylation patterns are involved in impaired glutamatergic signaling. Based on this scenario, this study aims to investigate histone 3 involvement in depression susceptibility or resilience in MDD pathophysiology by investigating cellular and molecular parameters related to i) glutamatergic neurotransmission, ii) astrocytic functioning, and iii) neurogenesis. For this, we subjected male Wistar rats to the Chronic Unpredictable Mild Stress (CUMS) model of depression. We propose that by evaluating the sucrose consumption, open field, and object recognition test performance from animals submitted to CUMS, it is possible to predict with high specificity rats with susceptibility to depressive-like phenotype and resilient to the depressive-like phenotype. We also demonstrated, for the first time, that patterns of H3K4me3, H3K9me3, H3K27me3, and H3K36me3 trimethylation are strictly associated with the resilient or susceptible to depressive-like phenotype in a brain-region-specific manner. Additionally, susceptible animals have reduced DCx and GFAP and resilient animals present increase of AQP-4 immunoreactivity. Together, these results provide evidence that H3 trimethylations are related to the development of the resilient or susceptible to depressive-like phenotype, contributing to further advances in the pathophysiology of MDD and the discovery of mechanisms behind resilience.
重度抑郁症（MDD）是一种严重的、多因素的精神疾病。证据表明，环境因素，如压力，在很大程度上解释了MDD的病理生理学。研究推测，组蛋白甲基化模式的变化与谷氨酸能信号传导受损有关。基于此，本研究旨在通过研究与以下方面相关的细胞和分子参数来探讨组蛋白3在MDD病理生理学中对抑郁易感性或恢复力的影响：i）谷氨酸能神经传递；ii）星形胶质细胞功能；iii）神经发生。为此，我们将雄性Wistar大鼠置于慢性不可预测轻度应激（CUMS）抑郁模型中。我们提出，通过评估接受CUMS的动物的蔗糖消耗、旷场试验和物体识别试验表现，可以高度特异性地预测易患抑郁样表型和对抑郁样表型具有恢复力的大鼠。我们还首次证明，H3K4me3、H3K9me3、H3K27me3和H3K36me3三甲基化模式以脑区特异性方式与对抑郁样表型的恢复力或易感性密切相关。此外，易患动物的双皮质素（DCx）和胶质纤维酸性蛋白（GFAP）减少，而具有恢复力的动物水通道蛋白4（AQP-4）免疫反应性增加。总之，这些结果提供了证据，表明H3三甲基化与对抑郁样表型的恢复力或易感性的发展有关，有助于MDD病理生理学的进一步进展以及恢复力背后机制的发现。
