From Inserm UMR894, Centre de Psychiatrie et Neuroscience, Paris F-75014 France; Université Paris Descartes, Sorbonne Paris Cité - Paris 5, France (Martin, Mathieu, Diaz, Salman, Alterio, Chevarin, Lanfumey, Hamon, Darmon, Masson); the College of Pharmacy, Idaho State University, Pocatello, ID 83209 USA (Austin); the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216 USA (Stockmeier); and Inserm UMR-S 1270, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer à Moulin, Paris, France (Darmon, Masson).
J Psychiatry Neurosci. 2020 Sep 1;45(5):344-355. doi: 10.1503/jpn.190134.
Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR trafficking may also be involved.
We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice.
Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys.
We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions.
These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.
血清素受体 1A（5-HT1AR）功能改变与焦虑、重度抑郁障碍以及抗抑郁药治疗抵抗密切相关。改变 5-HT1AR 功能的机制包括其表达的调节，但 5-HT1AR 的转运也可能参与其中。
我们研究了 Yif1B（5-HT1AR 转运蛋白）缺失对小鼠 5-HT 神经传递的影响，以及 Yif1B 表达是否会受到已知改变 5-HT 神经传递的条件的影响，如焦虑或抑郁状态，或在人类、猴子和小鼠中使用氟西汀（一种选择性 5-羟色胺再摄取抑制剂）治疗后。
与野生型小鼠相比，Yif1B 敲除小鼠的前脑 5-HT 投射纤维密度明显降低，而中缝核 5-HT 神经元表达的 5-HT1A 自身受体功能低下。此外，Yif1B 敲除小鼠的社交互动较少，对急性氟西汀注射的抗抑郁样作用没有反应。在野生型小鼠中，社会挫败与前额叶皮质中的 Yif1B mRNA 下调有关，而慢性氟西汀治疗会增加 Yif1B 的表达。在重度抑郁障碍患者的死后前额叶皮质中也观察到 Yif1B 的表达下调，而在猴子中接受选择性 5-羟色胺再摄取抑制剂的慢性治疗后则上调。
我们发现人类和猴子的 Yif1B 表达存在性别差异，但在测试条件下的小鼠中没有。
这些数据支持 Yif1B 在 5-HT1AR 功能和大脑 5-HT 稳态中发挥关键作用的概念。在焦虑或抑郁状态以及氟西汀治疗后观察到的表达相反变化表明，Yif1B 可能与焦虑和抑郁易感性以及氟西汀疗效有关。
