Tandem Pore Domain K+ channels (K2P) are accountable for K+ ‘leak’ currents in excitable cells and play a role in determining the excitability of neurons. In addition, the K2P subtype TASK-1 (KCNK3) is strongly pH-sensitive and may be a key regulator of neuronal damage during ischemia. Oligodendrocytes are the myelin-forming cells of the central nervous system (CNS) and are highly sensitive to ischemia. We have therefore examined whether oligodendrocytes express TASK-1 channels and if they have a function in ischemia. Mice were killed humanely in accordance with the UK Animals (Scientific Procedures) Act (1986) and brains or optic nerves removed for immunohistochemistry, tissue culture or electrophysiology. Immunohistochemistry of the cerebellum and optic nerve showed that TASK-1 is strongly expressed in oligodendrocyte somata and processes. Immunocytochemistry and whole cell patch-clamp of oligodendroglial cells cultured from mouse optic nerve explants demonstrated expression of TASK-1 channel protein and ionic currents with the properties of TASK-1 channels. Developing oligodendrocytes exhibit Kv and Kir currents, which when inhibited using a combination of extracellular (100 μM BaCl2, 3 mM tetraethylammonium chloride and 6 mM 4-aminopyridine) and intracellular (3 mM Na2ATP and 250 μM spermine) blockers revealed a residual outward K+ current that was sensitive to pHO and the TASK-1 inhibitor, anandamide. Peak outward currents were significantly lowered by 10 μM anandamide (p<0.05, t-test at +50 mV, n=7), and significantly increased at pH 8.4 compared to pH 6.4 (p<0.05, t-test at +100 mV, n=5). As a model for ischemic damage to oligodendrocytes, isolated intact optic nerves were subjected to oxygen-glucose deprivation (OGD) in an atmospheric chamber. Loss of oligodendrocyte processes was assessed by confocal microscope image analysis using transgenic fluorescent reporter mice (proteolipid protein (PLP) promoter driving dsRed or Sox10 promoter driving enhanced green fluorescence protein (EGFP) expression) and cell death assayed by propidium iodide staining. After 60 minutes of OGD there was a significant 36.12 ± 4.74% decrease in PLP+ oligodendrocyte processes compared to controls (p<0.05, ANOVA and Newman-Keuls post-hoc test, n=4) and a significant increase in oligodendrocyte cell death compared to controls (238.6 ± 44.1%, p<0.05, t-test, n=4). Treatment with methanandamide (10 µM) to inhibit TASK-1 during OGD prevented the loss of oligodendrocyte processes (p>0.05 vs control, n=4, p<0.05 vs OGD, n=4) and significantly protected against cell death (p>0.05 vs control, n=4, p<0.05 vs OGD, n=4). These results provide evidence of functional expression of TASK-1 in oligodendrocytes and indicate that TASK-1 channels are key mediators of oligodendrocyte damage and cell death during ischemia.