Bmal1-deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes
Bmal1-deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes
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DOI：
10.1002/glia.23754
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发表时间：
2019-11-19
期刊：
影响因子：
6.2
通讯作者：
von Gall, Charlotte
中科院分区：
文献类型：
--
作者：
Ali, Amira A. H.;Schwarz-Herzke, Beryl;von Gall, Charlotte
bmal 1是分子时钟的重要组成部分，它驱动细胞功能的昼夜节律。在Bmal 1缺陷（Bmal 1-/-）小鼠中，时间中断与认知缺陷和进行性脑病理学相关，包括胶质细胞酸性蛋白（GFAP）表达增加所指示的星形胶质细胞增多症。然而，相对知之甚少的影响Bmal 1缺乏对星形胶质细胞形态之前，星形胶质细胞。因此，在这项研究中，我们分析了年轻（6-8周龄）成年Bmal 1-/-小鼠的星形胶质细胞形态。在这个年龄，Bmal 1缺陷小鼠的GFAP免疫反应性总体上没有增加。在超微结构水平上，我们发现覆盖海马苔藓纤维突触的精细星形胶质细胞突起的体积分数减少，表明突触周突起及其对神经传递的贡献受损。为了进一步分析肌动蛋白细胞骨架，这是必不可少的远端过程的形成，我们使用培养的Bmal 1-/-星形胶质细胞。Bmal 1-/-星形胶质细胞肌动蛋白应力纤维的形成受损。此外，Bmal 1-/-星形胶质细胞表现出肌动蛋白结合蛋白coronin（CTTN）的水平降低。Cttn启动子区含有一个E-Box样元件，染色质免疫沉淀显示Cttn是一个潜在的Bmal 1靶基因。此外，GTP结合（活性）Rho-GTP酶（Rho-GTP）的水平在Bmal 1-/-星形胶质细胞中降低。总之，我们的数据表明，Bmal 1缺陷影响形态的精细星形胶质细胞过程之前，GFAP的强烈上调，大概是因为受损的Cttn表达和减少Rho-GTP激活。这些形态学变化可能会导致突触功能改变，从而与时间中断中的认知缺陷有关。
Bmal1 is an essential component of the molecular clockwork, which drives circadian rhythms in cell function. In Bmal1-deficient (Bmal1-/-) mice, chronodisruption is associated with cognitive deficits and progressive brain pathology including astrocytosis indicated by increased expression of glial fibrillary acidic protein (GFAP). However, relatively little is known about the impact of Bmal1-deficiency on astrocyte morphology prior to astrocytosis. Therefore, in this study we analysed astrocyte morphology in young (6-8 weeks old) adult Bmal1-/- mice. At this age, overall GFAP immunoreactivity was not increased in Bmal1-deficient mice. At the ultrastructural level, we found a decrease in the volume fraction of the fine astrocytic processes that cover the hippocampal mossy fiber synapse, suggesting an impairment of perisynaptic processes and their contribution to neurotransmission. For further analyses of actin cytoskeleton, which is essential for distal process formation, we used cultured Bmal1-/- astrocytes. Bmal1-/- astrocytes showed an impaired formation of actin stress fibers. Moreover, Bmal1-/- astrocytes showed reduced levels of the actin-binding protein cortactin (CTTN). Cttn promoter region contains an E-Box like element and chromatin immunoprecipitation revealed that Cttn is a potential Bmal1 target gene. In addition, the level of GTP-bound (active) Rho-GTPase (Rho-GTP) was reduced in Bmal1-/- astrocytes. In summary, our data demonstrate that Bmal1-deficiency affects morphology of the fine astrocyte processes prior to strong upregulation of GFAP, presumably because of impaired Cttn expression and reduced Rho-GTP activation. These morphological changes might result in altered synaptic function and, thereby, relate to cognitive deficits in chronodisruption.