Epigenetic modulation of antidepressant efficacy

描述（由申请人提供）：情绪障碍是全球残疾的第二大原因。他们的治疗主要依赖于靶向脑单胺的抗抑郁药物，包括选择性阿托宁再摄取抑制剂（SSRI）。然而，即使在长期治疗后，抗抑郁效果也有很大差异，只有一小部分患者表现出显著的治疗效果。由于情绪障碍的发病机制是复杂的，在具有相同诊断的个体中具有不同的遗传风险、环境影响和表观遗传表型的贡献，因此更“个性化治疗”的概念正在获得越来越大的动力，特别是对于具有早期生活压力（ELS）史的受试者，ELS是情绪障碍的突出风险因素，也是治疗反应不良的最强预测因子之一。该探索性建议针对这一患者人群的治疗，旨在将SSRIs的抗抑郁疗效与患者的表观遗传表型联系起来。该实验室最近的一项研究表明，暴露于ELS的应激敏感小鼠品系（Balb/c）表现出对ELS的适应性表观遗传反应，即额叶皮质中组蛋白H4蛋白乙酰化增加，从而改善了ELS的严重程度。 与ELS暴露相关的成人情感精神病理学。引人注目的是，ELS Balb/c小鼠的青少年氟西汀治疗产生了强大的抗抑郁作用，并进一步升高了乙酰化组蛋白H4蛋白的水平。这些发现激发了本文提出的对不同小鼠品系的行为和分子研究，这些研究检验了以下假设：氟西汀对组蛋白H4乙酰化的影响是抗抑郁药疗效的关键决定因素，增强的多巴胺能信号传导和降低的组蛋白脱乙酰酶（HDAC）活性导致了这种作用。对HDAC活性降低的ELS Balb/c小鼠的研究通过比较青少年治疗与抗抑郁药物的作用来研究增加的多巴胺能信号传导在刺激组蛋白H4乙酰化中的作用，所述抗抑郁药物增加脑中5-羟色胺（5-HT）水平（氟西汀）或不改变它们（噻奈普汀）。他们还研究了5-HT 1A和5-HT 2受体的作用以及脑源性神经营养因子介导的trkB信号在介导这种效应中的作用。对前脑5-HT水平升高且对氟西汀无反应的C57 B1/6降钙素转运蛋白敲除小鼠的其他研究调查了单独降低HDAC活性是否足以升高组蛋白H4乙酰化并挽救抗抑郁药治疗反应。最后，对另外两种对氟西汀具有低反应性的小鼠品系的研究测试了氟西汀和HDAC抑制剂的共同治疗是否增强抗抑郁作用，以及在青春期或成年期降低HDAC活性是否对组蛋白H4乙酰化和抗抑郁治疗反应具有相同的作用。在所有研究中，将探索药物诱导的脑中组蛋白H4乙酰化变化也存在于外周血淋巴细胞中的可能性。这些研究的积极结果可以确定一种能够预测抗抑郁药治疗反应的新生物标志物。

DESCRIPTION (provided by applicant): Mood disorders are the second leading cause of disability worldwide. Their treatment relies predominantly on antidepressant drugs that target brain monoamines, including selective serotonin-reuptake inhibitors (SSRIs). However, even after the prolonged treatment, the antidepressant effects vary considerably, with only a small faction of patients exhibiting significant treatment effects. Since the pathogenesis of mood disorders is complex, with different contributions of genetic risk, environmental influences, and epigenetic phenotypes in individuals with the same diagnosis, the concept of a more "personalized therapy" is gaining increasing momentum, especially for subjects with a history of early life stress (ELS), a prominent risk factor for mood disorders and one of the strongest predictors of poor treatment response. This exploratory proposal targets the treatment of this population of patients and aims at linking the antidepressant efficacy of SSRIs to the patient's epigenetic phenotype. A recent study from this laboratory showed that a stress-susceptible strain of mice (Balb/c) exposed to ELS exhibits an adaptive epigenetic response to ELS, namely increased acetylation of histone H4 protein in the frontal cortex, that ameliorates the severity of the adult emotional psychopathology associated with ELS exposure. Strikingly, adolescent fluoxetine treatment of ELS Balb/c mice exerted powerful antidepressant effects and further elevated levels of acetylated histone H4 protein. These findings motivated the behavioral and molecular studies on different mouse strains proposed here that test the hypothesis that the effect of fluoxetine on histone H4 acetylation is a critical determinant of antidepressant efficacy and that enhanced serotonergic signaling and reduced activity of histone deacetylases (HDACs) lead to this effect. Studies on ELS Balb/c mice with reduced HDAC activity investigate the role of increased serotonergic signaling in stimulating histone H4 acetylation by comparing the effects of adolescent treatments with antidepressant drugs that either increase serotonin (5-HT) levels in the brain (fluoxetine) or that do not alter them (tianeptine). They also examine the role of 5-HT1A and 5-HT2 receptors as well as the role of brain derived neurotrophic factor-mediated trkB-signaling in mediating this effect. Additional studies on C57Bl/6 serotonin-transporter knockout mice with elevated forebrain 5-HT levels and no response to fluoxetine investigate whether reducing HDAC activity alone is sufficient to elevate histone H4 acetylation and to rescue antidepressant treatment response. Finally, studies on two additional strains of mice with low responsiveness to fluoxetine test whether co-treatment with fluoxetine and an HDAC inhibitor enhances antidepressant effects, and whether reducing HDAC activity during adolescence or adulthood has the same effect on histone H4 acetylation and antidepressant treatment response. In all studies, the possibility that drug-induced changes in histone H4 acetylation in brain are also found in peripheral blood lymphocytes will be explored. Positive results from these studies could identify a new biomarker capable of predicting antidepressant treatment response.