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Voltage\u2010gated proton channel (Hv1) is expressed in microglia and contributes to nicotinamide adenine dinucleotide phosphate oxidase complex\u2010dependent production of reactive oxygen species (ROS). Recent findings have shown that Hv1 is involved in regulating luminal pH of M1\u2010polarized microglial phagosomes and inhibits endocytosis in microglia. We previously reported that Hv1 facilitated production of ROS and pro\u2010inflammatory cytokines in microglia and enhanced damage to oligodendrocyte progenitor cells from oxygen and glucose deprivation. To investigate the role of Hv1 in hypoperfusion\u2010induced WMI, we employed mice that were genetically devoid of Hv1 (Hv1<jats:sup>\u2010\/\u2010<\/jats:sup>), as well as a model of subcortical vascular dementia via bilateral common carotid artery stenosis. Integrity of myelin was assessed using immunofluorescent staining and transmission electron microscopy, while cognitive impairment was assessed using an eight\u2010arm radial maze test. Hv1 deficiency was found to attenuate bilateral common carotid artery stenosis\u2010induced disruption of white matter integrity and impairment of working memory. Immunofluorescent staining and western blotting were used to assay changes in oligodendrocytes, OPCs, and microglial polarization. Compared with that in wild\u2010type (WT) mice, Hv1<jats:sup>\u2010\/\u2010<\/jats:sup> mice exhibited reduced ROS generation, decreased pro\u2010inflammatory cytokines production, and an M2\u2010dominant rather than M1\u2010dominant microglial polarization. Furthermore, Hv1<jats:sup>\u2010\/\u2010<\/jats:sup> mice exhibited enhanced OPC proliferation and differentiation into oligodendrocytes. Results of mouse\u2010derived microglia\u2010OPC co\u2010cultures suggested that PI3K\/Akt signaling was involved in Hv1\u2010deficiency\u2010induced M2\u2010type microglial polarization and concomitant OPC differentiation. These results suggest that microglial Hv1 is a promising therapeutic target for reducing ischemic WMI and cognitive impairment.<\/jats:p>","DOI":"10.1111\/jnc.14925","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T13:17:22Z","timestamp":1574774242000},"page":"350-367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Microglial Hv1 proton channels promote white matter injuries after chronic hypoperfusion in mice"],"prefix":"10.1111","volume":"152","author":[{"given":"Ying","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Neurology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurology Tongji Hospital Tongji Medical College Huazhong University of Science and 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