Schacke Stephan, Kirkpatrick Joanna, Stocksdale Amy, Bauer Reinhard, Hagel Christian, Riecken Lars Björn, Morrison Helen
Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany.
Glia. 2022 Dec;70(12):2309-2329. doi: 10.1002/glia.24253. Epub 2022 Aug 5.
Astrocytes are increasingly being recognized as contributors to physiological brain function and behavior. Astrocytes engage in glia-synaptic interactions through peripheral astrocyte processes, thus modulating synaptic signaling, for example, by handling glutamate removal from the synaptic cleft and (re)provision to axonal terminals. Peripheral astrocyte processes are ultrafine membrane protrusions rich in the membrane-to-actin cytoskeleton linker Ezrin, an essential component of in vitro filopodia formation and in vivo peripheral astrocyte process motility. Consequently, it has been postulated that Ezrin significantly contributes to neurodevelopment as well as astrocyte functions within the adult brain. However, while Ezrin has been studied in vitro within cultured primary astrocytes, in vivo studies on the role of Ezrin in astrocytes remain to be conducted and consequences of its depletion to be studied. Here, we investigated consequences of Ezrin deletion in the mouse brain starting from early neuronal specification. While Ezrin knockout did not impact prenatal cerebral cortex development, behavioral phenotyping depicted reduced exploratory behavior. Starting with postnatal appearance of glia cells, Ezrin was verified to remain predominantly expressed in astrocytes. Proteome analysis of Ezrin deficient astrocytes revealed alterations in glutamate and ion homeostasis, metabolism and cell morphology - important processes for synaptic signal transmission. Notably, Ezrin deletion in astrocytes provoked (GFAP) glial fibrillary acidic protein upregulation - a marker of astrocyte activation and reactive astrogliosis. However, this spontaneous, reactive astrogliosis exhibited proteome changes distinct from ischemic-induced reactive astrogliosis. Moreover, in experimental ischemic stroke, Ezrin knockout mice displayed reduced infarct volume, indicating a protective effect of the Ezrin deletion-induced changes and astrogliosis.
星形胶质细胞越来越被认为是生理性脑功能和行为的贡献者。星形胶质细胞通过外周星形胶质细胞突起参与胶质-突触相互作用，从而调节突触信号，例如，通过处理从突触间隙清除谷氨酸并（重新）提供给轴突终末。外周星形胶质细胞突起是富含膜-肌动蛋白细胞骨架连接蛋白埃兹蛋白（Ezrin）的超微膜突起，埃兹蛋白是体外丝状伪足形成和体内外周星形胶质细胞突起运动的重要组成部分。因此，据推测埃兹蛋白对神经发育以及成人大脑内的星形胶质细胞功能有显著贡献。然而，虽然已经在培养的原代星形胶质细胞中对埃兹蛋白进行了体外研究，但关于埃兹蛋白在星形胶质细胞中的作用的体内研究仍有待开展，其缺失的后果也有待研究。在这里，我们从早期神经元特化开始研究小鼠脑中埃兹蛋白缺失的后果。虽然埃兹蛋白敲除不影响产前大脑皮质发育，但行为表型分析显示探索行为减少。从出生后胶质细胞出现开始，证实埃兹蛋白主要在星形胶质细胞中表达。对埃兹蛋白缺陷型星形胶质细胞的蛋白质组分析揭示了谷氨酸和离子稳态、代谢及细胞形态的改变，这些都是突触信号传递的重要过程。值得注意的是，星形胶质细胞中埃兹蛋白的缺失引发了胶质纤维酸性蛋白（GFAP）上调，这是星形胶质细胞活化和反应性星形胶质化的标志物。然而，这种自发的反应性星形胶质化表现出与缺血诱导的反应性星形胶质化不同的蛋白质组变化。此外，在实验性缺血性卒中中，埃兹蛋白敲除小鼠的梗死体积减小，表明埃兹蛋白缺失诱导的变化和星形胶质化具有保护作用。
