PDF(Pubmed)
Abstract：
Glycine receptors (GlyRs) are ligand-gated chloride channels comprising alpha (α1-4) and β subunits. The GlyR subunits play major roles in the mammalian central nervous system, ranging from regulating simple sensory information to modulating higher-order brain function. Unlike the other GlyR subunits, GlyR α4 receives relatively little attention because the human ortholog lacks a transmembrane domain and is thus considered a pseudogene. A recent genetic study reported that the GLRA4 pseudogene locus on the X chromosome is potentially involved in cognitive impairment, motor delay and craniofacial anomalies in humans. The physiologic roles of GlyR α4 in mammal behavior and its involvement in disease, however, are not known. Here we examined the temporal and spatial expression profile of GlyR α4 in the mouse brain and subjected Glra4 mutant mice to a comprehensive behavioral analysis to elucidate the role of GlyR α4 in behavior. The GlyR α4 subunit was mainly enriched in the hindbrain and midbrain, and had relatively lower expression in the thalamus, cerebellum, hypothalamus, and olfactory bulb. In addition, expression of the GlyR α4 subunit gradually increased during brain development. Glra4 mutant mice exhibited a decreased amplitude and delayed onset of the startle response compared with wild-type littermates, and increased social interaction in the home cage during the dark period. Glra4 mutants also had a low percentage of entries into open arms in the elevated plus-maze test. Although mice with GlyR α4 deficiency did not show motor and learning abnormalities reported to be associated in human genomics studies, they exhibited behavioral changes in startle response and social and anxiety-like behavior. Our data clarify the spatiotemporal expression pattern of the GlyR α4 subunit and suggest that glycinergic signaling modulates social, startle, and anxiety-like behaviors in mice.
摘要：
甘氨酸受体(GlyRs)是包含α(α1-4)和β亚基的配体门控氯通道。GlyR亚基在哺乳动物中枢神经系统中发挥重要作用,从调节简单的感觉信息到调节高阶大脑功能。与其他GlyR亚基不同，GlyRα4受到的关注相对较少，因为人类直系同源物缺乏跨膜结构域，因此被认为是假基因。最近的一项遗传学研究报道，X染色体上的GLRA4假基因位点可能与认知障碍有关，人类的运动延迟和颅面异常。GlyRα4在哺乳动物行为中的生理作用及其在疾病中的参与，然而,不知道。在这里，我们检查了GlyRα4在小鼠大脑中的时空表达谱，并对Glra4突变小鼠进行了全面的行为分析，以阐明GlyRα4在行为中的作用。GlyRα4亚基主要富集在后脑和中脑,在丘脑中的表达相对较低，小脑,下丘脑,和嗅觉灯泡。此外,GlyRα4亚基的表达在大脑发育过程中逐渐增加。与野生型同窝动物相比，Glra4突变小鼠表现出惊吓反应的振幅降低和延迟发作，并在黑暗时期增加了家庭笼子中的社交互动。在高架迷宫测试中，Glra4突变体进入开放臂的百分比也很低。尽管GlyRα4缺乏的小鼠在人类基因组学研究中没有显示运动和学习异常，他们表现出惊吓反应以及社交和焦虑样行为的行为变化。我们的数据阐明了GlyRα4亚基的时空表达模式，并表明甘氨酸能信号调节社会，惊吓,和老鼠的焦虑样行为。
