Department of Developmental Molecular Anatomy, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Neuroscience. 2012 Dec 13;226:119-29. doi: 10.1016/j.neuroscience.2012.08.068. Epub 2012 Sep 12.
S100A6 (calcyclin), an EF-hand calcium binding protein, is considered to exert various functions, e.g., cell proliferation and differentiation, calcium homeostasis, and neuronal degeneration. In this study, we aimed to investigate whether S100A6 might be linked to glutamate toxicity using three animal models and pharmacological interventions. We first examined the age-related changes in S100A6 immunoreactivity in the mouse hippocampus, considering that an important negative aspect of brain aging is linked to increased extracellular glutamate. The surface area of S100A6-positive (+) astrocytes was significantly larger in aged mice than in young mice, while the numbers of S100β+ astrocytes did not change with age. In the second experiment, we examined the alterations in S100A6 immunoreactivity in the injured hypoglossal nucleus, because glutamate toxicity is considered to contribute to neuronal death after axotomy. There was no apparent S100A6 immunoreactivity in the hypoglossal nucleus of sham control animals. However, intense labeling for S100A6 in activated astrocytes was observed in the axotomized hypoglossal nucleus of mice. Administration of ceftriaxone, an astrocyte glutamate transporter enhancer, to axotomized mice significantly decreased the immunoreactivity for S100A6. In the third experiment, we tested an animal model of epilepsy using kainic acid (KA), a glutamate analog. In the mouse hippocampus after KA injection, S100A6 immunoreactivity was significantly increased in astrocytes, and pyknotic changes were observed in CA3 pyramidal neurons. Treatment of MK-801, an N-methyl-d-aspartate receptor antagonist, counteracted the KA-induced increase in S100A6 immunoreactivity, and reduced the numbers of pyknotic neurons. Our results indicate that upregulation of astrocytic S100A6 in response to extracellular glutamate may be involved in neuronal damage under pathophysiological conditions.
S100A6（钙粒蛋白）是一种 EF 手钙结合蛋白，被认为具有多种功能，例如细胞增殖和分化、钙稳态和神经元变性。在这项研究中，我们旨在使用三种动物模型和药理学干预来研究 S100A6 是否与谷氨酸毒性有关。我们首先检查了 S100A6 免疫反应性在小鼠海马体中的年龄相关变化，因为大脑老化的一个重要负面方面与细胞外谷氨酸的增加有关。与年轻小鼠相比，老年小鼠中 S100A6 阳性（+）星形胶质细胞的表面积明显更大，而 S100β+星形胶质细胞的数量不随年龄而变化。在第二个实验中，我们检查了损伤舌下神经核中 S100A6 免疫反应性的改变，因为谷氨酸毒性被认为有助于轴突切断后的神经元死亡。假手术对照动物的舌下神经核中没有明显的 S100A6 免疫反应性。然而，在小鼠的舌下神经核中，观察到被激活的星形胶质细胞中 S100A6 的强烈标记。在切断的舌下神经核中给予头孢曲松（一种星形胶质细胞谷氨酸转运体增强剂）显著降低了 S100A6 的免疫反应性。在第三个实验中，我们使用谷氨酸类似物海人酸（KA）测试了一种癫痫动物模型。在 KA 注射后的小鼠海马体中，S100A6 免疫反应性在星形胶质细胞中显著增加，并且 CA3 锥体神经元出现固缩变化。N-甲基-D-天冬氨酸受体拮抗剂 MK-801 的治疗减轻了 KA 诱导的 S100A6 免疫反应性增加，并减少了固缩神经元的数量。我们的结果表明，在病理生理条件下，细胞外谷氨酸引起的星形胶质细胞 S100A6 的上调可能与神经元损伤有关。
