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首页> 外文期刊>The European Journal of Neuroscience >Increased vulnerability to kainate-induced seizures in utrophin-knockout mice.
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Increased vulnerability to kainate-induced seizures in utrophin-knockout mice.

机译：促性腺激素敲除小鼠对海藻酸盐诱导的癫痫发作的脆弱性增加。

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摘要

Utrophin, the autosomal homologue of dystrophin, the Duchenne muscular dystrophy gene product, is a cytoskeletal protein found in many tissues. In muscle fibers, the level and localization of utrophin depend on their state of differentiation and innervation. Transgenic overexpression of utrophin prevents degeneration of dystrophin-deficient muscle fibers. In brain, in addition to its enrichment in blood vessels, utrophin is associated primarily with the plasma membrane of large sensory and motor brainstem neurons, suggesting a contribution to their structural stability. Here, we examined the role of utrophin for long-term survival of dentate granule cells, which become markedly hypertrophic in a mouse model of temporal lobe epilepsy. This morphogenetic change is induced several weeks after a unilateral intrahippocampal injection of kainic acid (KA), while mice experience chronic focal seizures. Using in situ hybridization and immunohistochemistry, we show that dispersion and hypertrophy of granule cells in KA-treated wildtype mice are accompanied by a strong and long-lasting expression of utrophin in somata and proximal dendrites. Utrophin knockout mice had a normal hippocampal cytoarchitecture but were more sensitive to KA-induced excitotoxicity, as shown by increased mortality and faster progression of the lesion. At 6 weeks post-KA, the numerical density of granule cells and thickness of the granule cell layer were significantly reduced ipsilaterally in mutant mice, indicating a profound reduction in total cell number in the absence of utrophin. These findings suggest that utrophin contributes to protect CNS neurons against pathological insults, in particular, stimuli leading to massive neuronal hypertrophy.
机译：肌营养不良蛋白是肌营养不良蛋白的常染色体同源物，肌营养不良蛋白是杜兴氏肌营养不良症的基因产物，是一种在许多组织中发现的细胞骨架蛋白。在肌纤维中，卵磷脂的水平和位置取决于它们的分化和神经支配状态。促肾上腺皮质激素的转基因过度表达可防止肌营养不良蛋白缺乏的肌纤维变性。在脑中，除了增加其在血管中的含量外，促性腺激素还主要与大型感觉和运动性脑干神经元的质膜有关，提示对它们的结构稳定性有贡献。在这里，我们检查了卵磷脂在齿状颗粒细胞的长期存活中的作用，在颞叶癫痫的小鼠模型中，它们变得明显肥大。单侧海马内注射海藻酸（KA）后数周，诱导了这种形态发生变化，而小鼠则经历了慢性局灶性癫痫发作。使用原位杂交和免疫组化，我们显示在KA处理的野生型小鼠中颗粒细胞的分散和肥大与在躯体和近端树突中的卵磷脂的强烈而持久的表达有关。促肾上腺皮质激素敲除小鼠具有正常的海马细胞结构，但对KA诱导的兴奋性毒性更敏感，表现为病死率增加和病程进展加快。 KA后6周，在突变小鼠的同侧，颗粒细胞的数量密度和颗粒细胞层的厚度显着降低，这表明在缺乏促卵磷脂的情况下，总细胞数量明显减少。这些发现表明，促肾上腺皮质激素有助于保护中枢神经系统神经元免受病理损伤，特别是导致大量神经元肥大的刺激。

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