Cranial irradiation alters the behaviorally induced immediate-early gene arc (activity-regulated cytoskeleton-associated protein).
Cranial irradiation alters the behaviorally induced immediate-early gene arc (activity-regulated cytoskeleton-associated protein).
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DOI：
10.1158/0008-5472.can-08-1861
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Fike JR
中科院分区：
文献类型：
--
作者：
Rosi S;Andres-Mach M;Fishman KM;Levy W;Ferguson RA;Fike JR
脑部的治疗性照射通常用于治疗脑肿瘤，但可能导致严重影响生活质量的认知障碍。辐射引起认知缺陷的潜在机制尚不清楚，但可能涉及神经元活动的改变。为了深入了解辐射如何影响已知与认知功能相关的海马神经元，我们定量评估了行为诱导的即时早期基因（IEG） Arc（活性调节的细胞骨架相关蛋白）在mRNA和蛋白质水平上的分子分布。年轻成年C57BL/6小鼠分别接受0或10 Gy全脑照射，1周或2个月后探索新环境诱导Arc表达。采用荧光原位杂交（FISH）和免疫细胞化学分别检测表达Arc mRNA和Arc蛋白的神经元组分。我们的研究结果显示，照射后一周，表达Arc蛋白的神经元百分比显著减少，而照射后两个月，同时表达Arc mRNA和Arc蛋白的神经元百分比减少。重要的是，辐射诱导的Arc表达变化不是神经元细胞损失的结果。2个月时观察到的变化与激活的小胶质细胞数量的显著增加有关，支持炎症可能导致神经元功能障碍的观点。这些发现首次证明，局部脑照射会引发海马神经元的变化，破坏与神经可塑性和记忆相关的活动模式（Arc表达）。
Therapeutic irradiation of the brain is commonly used to treat brain tumors but can induce cognitive impairments that can severely affect quality of life. The underlying mechanisms responsible for radiation-induced cognitive deficits are unknown but likely involve alterations in neuronal activity. To gain some mechanistic insight into how irradiation may affect hippocampal neurons known to be associated with cognitive function, we quantitatively assessed the molecular distribution of the behaviorally-induced immediate early gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) at the level of mRNA and the protein. Young adult C57BL/6 mice received whole brain irradiation with 0 or 10 Gy, and 1 week or 2 months later, exploration of a novel environment was used to induce Arc expression. The fractions of neurons expressing Arc mRNA and Arc protein were detected using fluorescence in situ hybridization (FISH) and immunocytochemistry, respectively. Our results showed that there was a significant reduction in the percentage of neurons expressing Arc protein one week after irradiation, whereas two months after irradiation there was a reduction in the percentage of neurons expressing both Arc mRNA and Arc protein. Importantly, radiation induced changes in Arc expression were not a result of neuronal cell loss. The changes observed at 2 months were associated with a significant increase in the number of activated microglia, supporting the idea that inflammation may contribute to neuronal dysfunction. These findings are the first to demonstrate that local brain irradiation initiates changes in hippocampal neurons that disrupt the activity patterns (Arc expression) associated with neuroplasticity and memory.