The extent of an ischemic insult is less in brain regions enriched in astrocytes suggesting that astrocytes maintain function and buffer glutamate during ischemia. Astrocytes express a wide variety of potassium channels to support their functions including TREK-2 channels which are regulated by polyunsaturated fatty acids, intracellular acidosis and swelling; conditions that pertain to ischemia. The present study investigated the possible involvement of TREK-2 channels in cultured cortical astrocytes during experimental ischemia (anoxia/hypoglycemia) by examining TREK-2 protein levels, channel activity and ability to clear glutamate. We found that TREK-2 protein levels were increased rapidly within 2 hrs of the onset of simulated ischemia. This increase corresponded to an increase in temperature-sensitive TREK-2-like channel conductance and the ability of astrocytes to buffer extracellular glutamate even during ischemia. Together, these data suggest that up-regulation of TREK-2 channels may help rescue astrocyte function and lower extracellular glutamate during ischemia.