Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor
Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor
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DOI：
10.1016/j.brainres.2007.06.069
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发表时间：
2007-09-07
期刊：
影响因子：
2.9
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Chen, Yei-Tsung;Collins, Loretta L.;Chang, Chawnshang
自从睾丸孤儿核受体4(TR4)被克隆以来，其生理功能在很大程度上仍不清楚。本研究采用TR4基因敲除(TR4(-/-))小鼠模型，研究了TR4在成年小脑中的作用。在行为上，这些空白小鼠表现出不稳定的步态，以及不随意的姿势和运动，表明小脑功能障碍。在TR4(-/-)脑中，小脑局限性发育不良严重，小脑顶叶VI和VII发育不良，大脑皮层未见结构改变。对TR4(-/-)小脑皮质的组织学分析显示颗粒细胞密度减少，以及大小增大的平行纤维突起数量减少。进一步的分析表明，在小脑的浦肯野细胞和中间神经元中，GABA和GAD的水平都降低了，这表明小脑内部和来自小脑的抑制回路信号可能受到了干扰。此外，在TR4(-/-)小脑，浦肯野细胞GluR2/3免疫反应减弱，而小脑深核GluR2/3免疫反应增强。综上所述，这些结果表明，TR4(-/-)小鼠的行为表型可能是小脑抑制通路中断的结果。在不同成年期的TR4(-/-)脑中没有观察到进行性萎缩，因此，这种障碍很可能是由于在发育过程中小脑主要神经元之间未能建立适当的联系所致。(C)2007 Elsevier B.V.保留所有权利。
Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4(-/-)) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4(-/-) brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4(-/-) cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4(-/-) cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4(-/-) cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4(-/-) mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4(-/-) brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development. (C) 2007 Elsevier B.V. All rights reserved.