Effects of chronic antidepressants on mice with a mutation in Tph2

描述(申请人提供)：5-羟色胺(5-羟色胺)神经传递功能障碍与多种神经精神障碍有关。在抑郁症的治疗中，选择性5-羟色胺再摄取抑制剂(SSRIs)等抗抑郁药物的主要靶点是5-羟色胺(5-HT)神经传递。然而，患者对SSRIs的反应存在显著差异，只有一半的患者表现出完全缓解。此外，一些报告表明，SSRI治疗与某些患者自杀风险增加之间存在关联。该项目的长期目标是了解5-羟色胺、抗抑郁药物和行为之间的相互作用。在大脑中，合成5-羟色胺的限速步骤是由色氨酸羟基酶2(TPH2)催化的。最近在一组抑郁症患者中发现了人类TPH2的一个变种，并预测在PC12细胞系统中表达的突变体TPH2合成5-羟色胺的能力降低了80%。有趣的是，表达这种多态的患者对经典的抗抑郁药物治疗有抵抗力，这表明基因之间的相互作用和抗抑郁药物的治疗效果。在这个项目中，我们将使用表达人类TPH2变体的小鼠来测试5-羟色胺神经传递、行为和抗抑郁反应之间的相互作用。通过将人类TPH2突变基因工程到小鼠TPH2基因座上，已经产生了一个小鼠品系。TPH2基因敲入(TPH2Ki)小鼠概括了预测的大脑不同区域5-羟色胺合成减少80%。在这项建议中，TPH2Ki小鼠将接受抗抑郁药物的长期治疗，以确定SSRI如何影响它们的神经化学和行为测量的抑郁和焦虑以及生化相关性。我们还将尝试通过用5-羟色氨酸前体5-羟色氨酸治疗TPH2Ki小鼠来逆转抗抑郁治疗的任何异常效果。公共卫生相关性：该项目的目的是证明基因在抗抑郁药物治疗有效性中的重要性。我们打算证明，经典的抗抑郁药物并不是治疗某些基因突变患者的最佳形式。事实上，带有一些基因突变的患者可能会对抗抑郁药物治疗产生不良反应。

DESCRIPTION (provided by applicant): Dysfunction of serotonin (5-HT) neurotransmission is implicated in a variety of neuropsychiatric disorders. In the treatment of depression, the primary target of antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) is 5-HT neurotransmission. However, there is significant variation in the response of patients to SSRIs with only half of patients showing full remission. Furthermore, several reports have suggested an association between SSRI treatment and an increased risk of suicide in some patients. The long-term objective of this project is to understand the interactions between 5-HT, antidepressants, and behavior. In the brain, the rate limiting step in the synthesis of 5-HT is catalyzed by the enzyme tryptophan hydroxylase 2 (Tph2). A variant in human Tph2 was recently identified in a cohort of patients with depression and predicted to reduce 5-HT synthesis by 80% based on the reduced ability of the mutant Tph2 to synthesize 5-HT when expressed in a PC12 cellular system. Interestingly, patients expressing this polymorphism were resistant to treatment with classical antidepressants, suggesting an interaction between genes and the effectiveness of antidepressant treatment. In this project, we will use mice expressing the human variant of Tph2 to test the interaction between 5-HT neurotransmission, behavior, and antidepressant response. A mouse line has already been generated by genetically engineering the human Tph2 mutation into the mouse Tph2 locus. Tph2 knock-in (Tph2 KI) mice recapitulate the predicted 80% decrease in 5-HT synthesis in various brain regions. In this proposal, the Tph2 KI mice will be treated chronically with antidepressants to determine how SSRIs affect their neurochemistry and behavioral measures of depression and anxiety as well as biochemical correlates. We will also attempt to reverse any abnormal effects of antidepressant treatment by treating the Tph2 KI mice with the 5-HT precursor, 5- hydroxytryptophan. PUBLIC HEALTH RELEVANCE: The aim of this project is to demonstrate the importance of genes in the effectiveness of antidepressant treatment. We intend to show that classical antidepressants are not the best form of treatment for patients with certain genetic mutations. In fact, patients with some genetic mutations may have adverse responses to antidepressant treatment.