Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-γ (IFN-γ) promote differentiation into classically activated M1-like microglia, which produce high levels of pro-inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL-4 in contrast induces a phenotype associated with anti-inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K⁺ channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL-4) microglia and studying their K⁺ channel expression by whole-cell patch-clamp, quantitative PCR and immunohistochemistry. We identified three major types of K⁺ channels based on their biophysical and pharmacological fingerprints: a use-dependent, outwardly rectifying current sensitive to the K_V 1.3 blockers PAP-1 and ShK-186, an inwardly rectifying Ba²⁺ -sensitive K_ir 2.1 current, and a Ca²⁺ -activated, TRAM-34-sensitive K_Ca 3.1 current. Both K_V 1.3 and K_Ca 3.1 blockers inhibited pro-inflammatory cytokine production and iNOS and COX2 expression demonstrating that K_V 1.3 and K_Ca 3.1 play important roles in microglia activation. Following differentiation with LPS or a combination of LPS and IFN-γ microglia exhibited high K_V 1.3 current densities (∼50 pA/pF at 40 mV) and virtually no K_Ca 3.1 and K_ir currents, while microglia differentiated with IL-4 exhibited large K_ir 2.1 currents (∼ 10 pA/pF at -120 mV). K_Ca 3.1 currents were generally low but moderately increased following stimulation with IFN-γ or ATP (∼10 pS/pF). This differential K⁺ channel expression pattern suggests that K_V 1.3 and K_Ca 3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions. GLIA 2016;65:106-121.

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