Effects of chronic antidepressants on mice with a mutation in Tph2

描述（由申请人提供）：5-羟色胺（5-HT）神经传递功能障碍与多种神经精神疾病有关。在抑郁症的治疗中，抗抑郁药如选择性5-羟色胺再摄取抑制剂（SSRIs）的主要目标是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化酶2 （Tph2）催化的。最近在一组抑郁症患者中发现了人类Tph2的一种变体，并预测该变体在PC12细胞系统中表达时合成5-HT的能力降低，从而使5-HT的合成减少80%。有趣的是，表达这种多态性的患者对传统抗抑郁药物治疗有抵抗力，这表明基因与抗抑郁药物治疗的有效性之间存在相互作用。在这个项目中，我们将使用表达人类Tph2变异的小鼠来测试5-HT神经传递、行为和抗抑郁反应之间的相互作用。通过基因工程将人类Tph2突变植入小鼠Tph2位点，已经产生了一个小鼠品系。Tph2敲入（Tph2 KI）小鼠重现了预测的大脑各区域5-HT合成减少80%。在这项提议中，Tph2 KI小鼠将长期接受抗抑郁药治疗，以确定SSRIs如何影响其抑郁和焦虑的神经化学和行为测量以及生化相关因素。我们还将尝试通过用5-羟色氨酸前体治疗Tph2 KI小鼠来逆转抗抑郁药物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治疗有效性中的重要性。我们想要证明，传统的抗抑郁药并不是治疗某些基因突变患者的最佳方式。事实上，一些基因突变的患者可能对抗抑郁药物治疗有不良反应。

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.