First Author | Wei T | Year | 2019 |
Journal | Neurobiol Dis | Volume | 132 |
Pages | 104588 | PubMed ID | 31470105 |
Mgi Jnum | J:282633 | Mgi Id | MGI:6381876 |
Doi | 10.1016/j.nbd.2019.104588 | Citation | Wei T, et al. (2019) KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3beta pathway. Neurobiol Dis 132:104588 |
abstractText | Neuroinflammation may induce a phenotype switch to reactive astrogliosis in neurodegenerative disorders. The calcium-activated potassium channel (KCa3.1) is active in the phenotypic switch that occurs during astrogliosis in Alzheimer''''s disease and ischemic stroke. Here, transcriptome sequencing (RNA-Seq), immunohistochemistry, western blotting, pharmacological blockade, and calcium imaging were used to investigate astrocyte KCa3.1 activity in neuroinflammation, Tau accumulation, and insulin signaling deficits in male wild-type C57BL/6 and KCa3.1(-/-) knockout (KO) mice, and in primary astrocyte cultures. KCa3.1 deficiency in KO mice decreased lipopolysaccharide (LPS)-induced memory deficits, neuronal loss, glial activation, Tau phosphorylation, and insulin signaling deficits in vivo. KCa3.1 expression in astrocytes was associated with LPS-induced upregulation of the Orai1 store-operated Ca(2+) channel protein. The KCa3.1 channel was found to regulate store-operated Ca(2+) overload through an interaction with Orai1 in LPS-induced reactive astrocytes. The LPS-induced effects on KCa3.1 and Orai1 indirectly promoted astrogliosis-related changes via the PI3K/AKT/GSK3beta and NF-kappaB signaling pathways in vitro. Unbiased evaluation of RNA-Seq results for actively translated RNAs confirmed that substantial astrocyte diversity was associated with KCa3.1 deficiency. Our results suggest that KCa3.1 regulated astrogliosis-mediated neuroinflammation, Tau accumulation, and insulin signaling deficiency via PI3K/AKT/GSK3beta and NF-kappaB signaling pathways, and contributing to neuronal loss and memory deficits in this neuroinflammation mouse model. |