Interactions Between Depression, Neuroinflammation and Glycogen Synthase Kinase-3

摘要 越来越多的证据表明，炎症强烈影响着疾病的发展和治疗 抑郁症是一种终生发病率约为20%的衰弱疾病。炎症标志物通常 在抑郁症患者的血清中，干扰素的应用会导致抑郁， 会导致抑郁的“心理”压力会增加人类体内的炎性细胞因子 啮齿动物，给予炎性细胞因子诱导啮齿动物抑郁样行为，在 人类增加与轻微刺激主要宿主防御系统相关的细胞因子 对情绪有负面影响，抗抑郁药有消炎作用，免疫 重度抑郁症患者的激活与抗抑郁药物治疗的抵抗有关。 因此，为了理解和设计改进的抑郁症治疗方法，重要的是 确定调节神经炎症的机制，炎症分子在中枢神经系统中的聚集。 糖原合成酶-3(GSK3)是近年来发现的一种强有力的细胞因子调节因子 外围地区的生产。我们将其扩展到中枢神经系统，例如，显示GSK3抑制剂可以减少 在星形胶质细胞和小胶质细胞中，90%的促炎细胞因子白介素6的产生。我们 还发现GSK3抑制剂促进了对炎症的耐受性，下调了炎症反应 对反复炎性刺激的反应，这在控制慢性炎症方面可能特别重要 可能与情绪障碍有关的炎症。GSK3在以下方面也具有深远的影响 情绪障碍，它被情绪稳定剂和抗抑郁剂抑制，药物或遗传的 GSK3活性降低可减少啮齿动物的抑郁样行为，并在死后得到证据 来自人类的大脑样本和血清表明，GSK3在情绪障碍中异常活跃。我们 最近发现，GSK3在小鼠的大脑中被获得性无助抑郁模型激活。 综上所述，这些发现表明GSK3的促炎作用可能有助于其 促进情绪障碍，以及情绪稳定剂和抗抑郁剂的治疗作用 抑制GSK3可能与抗炎作用有关。 因此，对炎症系统的研究为研究GSK3如何 调节可能与情绪障碍有关的关键过程：表观遗传学、耐受性和 行为。这些目标提供了独立但相关的目标，将通过以下方式确定新的机制 哪些调节失调的GSK3会导致情绪障碍，并确定治疗干预措施 改善这些结果。特定目标1将检验GSK3调节先天和 大脑中的适应性免疫系统在类似抑郁的行为中。《特定目标2》将测试 GSK3调控表观遗传学的假说，使用炎症刺激诱导的变化作为 模特。《特定目标3》将检验GSK3促进抑郁样行为的假设 对炎症和环境压力的反应。

ABSTRACT Accumulating evidence shows inflammation strongly influences the development and treatment of depression, a debilitating disease with a lifetime incidence of ~20%. Markers of Inflammation often are increased in the serum of depressed patients, interferon administration can induce depression, "psychological" stresses that can induce depression increase inflammatory cytokines in humans and rodents, administration of inflammatory cytokines induces depression-like behaviors in rodents, in humans increased cytokines associated with a mild stimulation of the primary host defense system has negative effects on emotions, antidepressants have anti-inflammatory effects, and immune activation in patients with major depression is associated with resistance to antidepressant treatment. Therefore, in order to understand and design improved therapeutics for depression, it is important to identify mechanisms regulating neuroinflammation, inflammatory molecule accumulation in the CNS. Glycogen synthase kinase-3 (GSK3) recently was found to be a powerful regulator of cytokine production in the periphery. We extended this to the CNS, e.g., showing that GSK3 inhibitors reduce by >90% the production of the proinflammatory cytokine interleukin-6 in astrocytes and microglia. We also found that GSK3 inhibitors promote tolerance to inflammation, down-regulating inflammatory responses to repeated inflammatory stimuli, which may be particularly important in controlling chronic inflammation that is likely associated with mood disorders. GSK3 also has profound influences in mood disorders, it is inhibited by mood stabilizers and antidepressants, pharmacological or genetic reduction of GSK3 activity reduces depression-like behaviors in rodents, and evidence in postmortem brain samples and serum from humans indicate GSK3 is abnormally active in mood disorders. We recently found GSK3 is activated in mouse brain by the learned helplessness model of depression. Taken together, these findings suggest that the pro-inflammatory action of GSK3 may contribute to its promotion of mood disorders, and that the therapeutic actions of mood stabilizers and antidepressants that inhibit GSK3 may involve anti-inflammatory effects. Thus, studies of the inflammation system provide a model system to study how GSK3 regulates key processes that are likely involved in mood disorders: epigenetics, tolerance, and behavior. These aims provide independent but associated goals that will identify new mechanisms by which dysregulated GSK3 can contribute to mood disorders and identify how therapeutic interventions ameliorate these outcomes. Specific Aim 1 will test the hypothesis that GSK3 regulates innate and adaptive immune system in the brain during depressive-like behavior. Specific Aim 2 will test the hypothesis that GSK3 regulates epigenetics, using changes induced by inflammatory stimuli as a model. Specific Aim 3 will test the hypothesis that GSK3 promotes depression-like behavioral responses to inflammatory and environmental stress.