Bentea Eduard, Demuyser Thomas, Van Liefferinge Joeri, Albertini Giulia, Deneyer Lauren, Nys Julie, Merckx Ellen, Michotte Yvette, Sato Hideyo, Arckens Lutgarde, Massie Ann, Smolders Ilse
Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jun 3;59:49-58. doi: 10.1016/j.pnpbp.2015.01.010. Epub 2015 Jan 23.
There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based tests (rotarod, adhesive removal test, nest building test). Finally, due to the presence and potential functional relevance of system xc- in the eye, we investigated the visual acuity of system xc- deficient mice (optomotor test). Our results indicate that loss of system xc- does not affect motor or sensorimotor function, in either adult or aged mice, in any of the paradigms investigated. Similarly, loss of system xc- does not affect basic visual acuity, in either adult or aged mice. On the other hand, in the open field and light/dark tests, and forced swim and tail suspension tests respectively, we could observe significant anxiolytic and antidepressive-like effects in system xc- deficient mice that in certain cases (light/dark, forced swim) were age-dependent. These findings indicate that, under physiological conditions, nonvesicular glutamate release via system xc- mediates aspects of higher brain function related to anxiety and depression, but does not influence sensorimotor function or spatial vision. As such, modulation of system xc- might constitute the basis of innovative interventions in mood disorders.
有大量临床前和临床证据表明，谷氨酸能信号的异常变化是情绪障碍发生发展的基础。特别是星形胶质细胞谷氨酸功能障碍，最近已与包括焦虑和抑郁在内的情绪障碍的发病机制和治疗联系起来。系统xc-是一种胶质细胞胱氨酸/谷氨酸反向转运体，负责大脑各个区域的非囊泡性谷氨酸释放。尽管系统xc-参与谷氨酸信号转导，但其在介导焦虑或抑郁样行为中的可能作用目前尚不清楚。在本研究中，我们对成年和老年系统xc-缺陷小鼠进行了一系列焦虑和抑郁样行为测试（旷场试验、明暗试验、高架十字迷宫试验、新奇抑制摄食试验、强迫游泳试验、悬尾试验）。同时，我们使用基于运动和感觉运动的测试（转棒试验、粘胶去除试验、筑巢试验）评估了系统xc-缺陷小鼠的感觉运动功能。最后，由于系统xc-在眼睛中的存在及其潜在的功能相关性，我们研究了系统xc-缺陷小鼠的视力（视动试验）。我们的结果表明，在任何研究的范式中，系统xc-的缺失在成年或老年小鼠中均不影响运动或感觉运动功能。同样，系统xc-的缺失在成年或老年小鼠中均不影响基本视力。另一方面，在旷场试验和明暗试验以及强迫游泳试验和悬尾试验中，我们分别观察到系统xc-缺陷小鼠有显著的抗焦虑和抗抑郁样作用，在某些情况下（明暗试验、强迫游泳试验）这些作用与年龄有关。这些发现表明，在生理条件下，通过系统xc-的非囊泡性谷氨酸释放介导与焦虑和抑郁相关的高级脑功能方面，但不影响感觉运动功能或空间视觉。因此，调节系统xc-可能构成情绪障碍创新干预的基础。
