KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3β pathway

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 Orail store-operated Ca2+ channel protein. The KCa3.1 channel was found to regulate store-operated Ca2+ overload through an interaction with Orail in LPS-induced reactive astrocytes. The LPS-induced effects on KCa3.1 and Orail indirectly promoted astrogliosis-related changes via the PI3K/AKT/GSK3 beta and NF-kappa B 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/GSK3 beta and NF-kappa B signaling pathways, and contributing to neuronal loss and memory deficits in this neuroinflammation mouse model.