Heterogeneity of microglial proton channel in different brain regions and its relationship with aging
Takafumi Kawai1, Keizo Takao2,3, Sharmin Akter1
1Integrative Physiology, Graduate School of Medicine & Frontier Biosciences, Osaka University, Suita, Japan.
Abstract:
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.
Insights
Microglia properties vary by age and brain region. The voltage-gated proton channel Hv1/VSOP influences brain oxidative stress, with its age-dependent effects most pronounced in the cortex, impacting anxiety in aged Hv1/VSOP-deficient mice.
Area of Science:
- Neuroscience
- Cell Biology
- Aging Research
Background:
- Microglia exhibit diverse properties influenced by aging and distinct brain regions.
- Functional heterogeneity of microglia at a molecular level remains understudied.
- The voltage-gated proton channel Hv1/VSOP regulates oxidative stress in an age-dependent manner, potentially contributing to microglial heterogeneity.
Purpose of the Study:
- To investigate the brain region-dependent heterogeneity of Hv1/VSOP expression in microglia.
- To examine the functional significance of Hv1/VSOP in the aging cerebral cortex and striatum.
- To assess the impact of aging on Hv1/VSOP function using behavioral analyses in deficient mice.
Main Methods:
- Analysis of Hv1/VSOP gene expression across different brain regions.
- Comparative studies of Hv1/VSOP in aged and young mice in the cortex and striatum, assessing oxidative stress, microglial morphology, and gene expression.
- Behavioral testing of Hv1/VSOP-deficient mice at young and aged stages.
Main Results:
- Hv1/VSOP gene expression demonstrated brain region-specific heterogeneity, highest in the striatum.
- In the cortex, Hv1/VSOP showed age-dependent effects on oxidative stress, microglial morphology, and gene expression.
- The age-dependent significance of Hv1/VSOP was less evident in the striatum compared to the cortex.
- Hv1/VSOP-deficient mice exhibited altered anxiety-like behavior in the light/dark transition test specifically at aged stages.
Conclusions:
- Hv1/VSOP exhibits distinct expression patterns across brain regions, contributing to microglial functional heterogeneity.
- The functional importance of Hv1/VSOP in microglia is modulated by both brain region and animal age.
- Aging affects Hv1/VSOP's role in the cortex more significantly than in the striatum, influencing anxiety-related behaviors in aged deficient mice.
