Takemiya Takako, Fumizawa Kumiko, Yamagata Kanato, Iwakura Yoichiro, Kawakami Marumi
Medical Research Institute, Tokyo Women's Medical University, Tokyo, Japan.
Synaptic Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Front Behav Neurosci. 2017 Oct 23;11:202. doi: 10.3389/fnbeh.2017.00202. eCollection 2017.
The proinflammatory cytokine interleukin-1 (IL-1) is produced by many types of cells, including immune cells in the periphery and glia and neurons in the brain. The type I IL-1 receptor (IL-1r1) is primarily responsible for transmitting the inflammatory effects of IL-1 and mediates several biological functions by binding to either IL-1α or IL-1β. IL-1β activation is associated with hippocampus-dependent memory tasks. Although IL-1β impairs spatial memory under certain pathophysiological conditions, IL-1β may be required for the normal physiological regulation of hippocampal plasticity and memory. In addition, brain IL-1β levels are thought to change in the hippocampus in an age-dependent manner. These findings suggest that IL-1β may have a beneficial, temporary effect on learning and memory in young mice, but the matter remains unclear. Therefore, we hypothesized that hippocampal IL-1β has a beneficial effect on spatial learning and memory in young mice via IL-1r1, which is diminished in adults. We investigated the performance of young (3-month-old) and adult (6-month-old) wild-type mice, IL-1β knockout mice (IL-1βko) and IL-1r1 knockout mice (IL-1r1ko) in learning a spatial memory task with a fixed platform in a water maze (WM) and measured the levels of IL-1β and IL-1α in the hippocampus and cortex of adult and young mice by using homogeneous time-resolved fluorescence (HTRF). Learning was significantly impaired in the training trials of the WM spatial memory task in young IL-1βko and IL-1r1ko mice but not in adult IL-1βko and IL-1r1ko mice. Moreover, young IL-1r1ko mice but not IL-1βko mice showed an impairment in long-term memory extinction, suggesting that IL-1α might facilitate memory extinction. In this study, the cytokine assay using HTRF did not indicate a higher expression of hippocampal IL-1 in young mice but cortical IL-1β and IL-1α were significantly increased in adult mice. We need to investigate the role of cortical IL-1 and the local IL-1 expression in the hippocampal neurons in the future.
促炎细胞因子白细胞介素-1（IL-1）由多种类型的细胞产生，包括外周免疫细胞以及脑内的神经胶质细胞和神经元。I型白细胞介素-1受体（IL-1r1）主要负责传递IL-1的炎症效应，并通过与IL-1α或IL-1β结合介导多种生物学功能。IL-1β的激活与依赖海马体的记忆任务相关。尽管在某些病理生理条件下IL-1β会损害空间记忆，但海马体可塑性和记忆的正常生理调节可能需要IL-1β。此外，脑内IL-1β水平被认为会以年龄依赖的方式在海马体中发生变化。这些发现表明IL-1β可能对幼鼠的学习和记忆有有益的、暂时的影响，但情况仍不明确。因此，我们假设海马体IL-1β通过IL-1r1对幼鼠的空间学习和记忆有有益影响，而在成年鼠中这种影响会减弱。我们研究了幼年（3个月大）和成年（6个月大）野生型小鼠、IL-1β基因敲除小鼠（IL-1βko）和IL-1r1基因敲除小鼠（IL-1r1ko）在水迷宫（WM）中学习固定平台空间记忆任务的表现，并使用均相时间分辨荧光（HTRF）测量成年和幼年小鼠海马体及皮质中IL-1β和IL-1α的水平。在WM空间记忆任务的训练试验中，幼年IL-1βko和IL-1r1ko小鼠的学习能力显著受损，但成年IL-1βko和IL-1r1ko小鼠未出现这种情况。此外，幼年IL-1r1ko小鼠而非IL-1βko小鼠在长期记忆消退方面存在缺陷，这表明IL-1α可能促进记忆消退。在本研究中，使用HTRF进行的细胞因子检测未显示幼鼠海马体中IL-1的表达更高，但成年鼠皮质中的IL-1β和IL-1α显著增加。未来我们需要研究皮质IL-1的作用以及海马体神经元中局部IL-1的表达情况。
