Rosi Susanna, Andres-Mach Marta, Fishman Kelly M, Levy William, Ferguson Ryan A, Fike John R
Brain and Spinal Injury Center, Department of Physical Therapy and Rehabilitation Sciences, University of California, San Francisco, San Francisco, California 94110, USA.
Cancer Res. 2008 Dec 1;68(23):9763-70. doi: 10.1158/0008-5472.CAN-08-1861.
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 Arc (activity-regulated cytoskeleton-associated protein) at the level of mRNA and the protein. Young adult C57BL/6J 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 and immunocytochemistry, respectively. Our results showed that there was a significant reduction in the percentage of neurons expressing Arc protein 1 week after irradiation, whereas 2 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 show that local brain irradiation initiates changes in hippocampal neurons that disrupt the activity patterns (Arc expression) associated with neuroplasticity and memory.
脑部治疗性放射常用于治疗脑肿瘤，但可能会引发认知障碍，严重影响生活质量。辐射诱发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，我们在mRNA和蛋白质水平定量评估了行为诱导的即刻早期基因Arc（活性调节细胞骨架相关蛋白）的分子分布。年轻成年C57BL/6J小鼠接受0或10 Gy的全脑照射，1周或2个月后，利用探索新环境来诱导Arc表达。分别使用荧光原位杂交和免疫细胞化学检测表达Arc mRNA和Arc蛋白的神经元比例。我们的结果表明，照射后1周，表达Arc蛋白的神经元百分比显著降低，而照射后2个月，表达Arc mRNA和Arc蛋白的神经元百分比均降低。重要的是，辐射诱导的Arc表达变化并非神经元细胞丢失的结果。在2个月时观察到的变化与活化小胶质细胞数量的显著增加有关，这支持了炎症可能导致神经元功能障碍的观点。这些发现首次表明，局部脑部照射会引发海马神经元的变化，扰乱与神经可塑性和记忆相关的活动模式（Arc表达）。
