Integrative Physiology, Graduate School of Medicine & Frontier Biosciences, Osaka University, Suita, Japan.
Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan.
J Neurochem. 2021 May;157(3):624-641. doi: 10.1111/jnc.15292. Epub 2021 Jan 20.
The properties of microglia largely differ depending on aging as well as on brain regions. However, there are few studies that investigated the functional importance of such heterogeneous properties of microglia at the molecular level. Voltage-gated proton channel, Hv1/VSOP, could be one of the candidates which confers functional heterogeneity among microglia since it regulates brain oxidative stress in age-dependent manner. In this study, we found that Hv1/VSOP shows brain region-dependent heterogeneity of gene expression with the highest level in the striatum. We studied the importance of Hv1/VSOP in two different brain regions, the cerebral cortex and striatum, and examined their relationship with aging (using mice of different ages). In the cortex, we observed the age-dependent impact of Hv1/VSOP on oxidative stress, microglial morphology, and gene expression profile. On the other hand, we found that the age-dependent significance of Hv1/VSOP was less obvious in the striatum than the cortex. Finally, we performed a battery of behavioral experiments on Hv1/VSOP-deficient mice both at young and aged stages to examine the effect of aging on Hv1/VSOP function. Hv1/VSOP-deficient mice specifically showed a marked difference in behavior in light/dark transition test only at aged stages, indicating that anxiety state is altered in aged Hv1/VSOP mice. This study suggests that a combination of brain region heterogeneity and animal aging underscores the functional importance of Hv1/VSOP in microglia.
小胶质细胞的特性在很大程度上取决于衰老和大脑区域。然而，很少有研究从分子水平上研究小胶质细胞这种异质性特性的功能重要性。电压门控质子通道 Hv1/VSOP 可能是赋予小胶质细胞功能异质性的候选者之一，因为它以依赖于年龄的方式调节大脑氧化应激。在这项研究中，我们发现 Hv1/VSOP 在大脑区域中表现出基因表达的依赖性异质性，在纹状体中表达水平最高。我们研究了 Hv1/VSOP 在两个不同大脑区域（大脑皮层和纹状体）中的重要性，并检查了它们与衰老的关系（使用不同年龄的小鼠）。在皮层中，我们观察到 Hv1/VSOP 对氧化应激、小胶质细胞形态和基因表达谱的年龄依赖性影响。另一方面，我们发现 Hv1/VSOP 在纹状体中的年龄依赖性意义不如在皮层中明显。最后，我们在年轻和年老阶段对 Hv1/VSOP 缺陷小鼠进行了一系列行为实验，以检查衰老对 Hv1/VSOP 功能的影响。Hv1/VSOP 缺陷小鼠仅在年老阶段的明暗转换测试中表现出明显的行为差异，表明年老 Hv1/VSOP 小鼠的焦虑状态发生了改变。这项研究表明，大脑区域异质性和动物衰老的结合突显了 Hv1/VSOP 在小胶质细胞中的功能重要性。
