Epigenetic modulation of antidepressant efficacy

描述(申请人提供)：情绪障碍是全球第二大致残原因。他们的治疗主要依赖于针对大脑单胺的抗抑郁药物，包括选择性5-羟色胺再摄取抑制剂(SSRIs)。然而，即使在延长治疗后，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。由于心境障碍的发病机制是复杂的，在相同诊断的个体中，遗传风险、环境影响和表观遗传表型的不同贡献，更多的个性化治疗的概念正在获得动力，特别是对于有早期生活应激(ELS)病史的受试者，这是情绪障碍的一个突出的风险因素，也是治疗反应差的最强预测因素之一。这项探索性建议针对的是这类患者的治疗，旨在将SSRIs的抗抑郁疗效与患者的表观遗传表型联系起来。本实验室最近的一项研究表明，暴露于ELS的一种应激敏感品系(Balb/c)对ELS表现出适应性表观遗传反应，即额叶皮质中组蛋白H4乙酰化增加，从而减轻了ELS的严重程度。 与ELS暴露相关的成人情绪心理病理。值得注意的是，青春期氟西汀对ELS Balb/c小鼠产生了强大的抗抑郁作用，并进一步提高了乙酰化组蛋白H4的水平。这些发现推动了对不同品系小鼠的行为和分子研究，这些研究验证了这样的假设，即氟西汀对组蛋白H4乙酰化的影响是抗抑郁疗效的关键决定因素，并且5-羟色胺能信号增强和组蛋白脱乙酰酶(HDACs)活性降低导致这种效应。对HDAC活性降低的ELS Balb/c小鼠进行的研究通过比较青春期治疗与提高大脑5-羟色胺(5-HT)水平的抗抑郁药物(氟西汀)或不改变5-羟色胺水平(替尼普汀)的效果，探讨5-羟色胺能信号增加在刺激组蛋白H4乙酰化中的作用。他们还研究了5-HT1a和5-HT2受体的作用，以及脑源性神经营养因子介导的TrkB信号在介导这一效应中的作用。对前脑5-羟色胺水平升高且对氟西汀无反应的C57BL/6 5-羟色胺转运体基因敲除小鼠进行的其他研究调查了仅降低HDAC活性是否足以提高组蛋白H4乙酰化并挽救抗抑郁药物的治疗反应。最后，对另外两种对氟西汀反应性低的小鼠的研究，测试了与氟西汀和HDAC抑制剂联合治疗是否增强了抗抑郁效果，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影响。在所有的研究中，都将探索药物引起的脑内组蛋白H4乙酰化的改变在外周血淋巴细胞中也存在的可能性。这些研究的阳性结果可能确定一种新的生物标记物，能够预测抗抑郁药物的治疗反应。

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.