Cell death in cerebral ischemia is presumably initiated by neural exciotoxicity resulted from the dysfunction of inhibitory neurons in early stage Molecular processes underlying the ischemic injury of inhibitory neurons remain to be elusive, which we investigated by biochemical manipulations with cellular imaging and patch clamp at GFP-labeled GABAergic cells in cortical slices. Ischemia induces Ca2+ elevation, acidosis and dysfunction in GABAergic cells An elevation of cytoplasmic Ca2+ or H+ impairs the encoding of action potentials in these neurons The effects of Ca2+ and H+ are additive in nature and occlude ischemic outcomes Ischemia impairs spike production through prolonging spike refractory periods and raising threshold potentials Therefore, calcium toxicity and acidosis during ischemia synergistically impair the dynamics of sodium channels and function of cortical GABAergic neurons, which lead to neural excitotoxicity. Our results also suggest that the cocktail therapeutics is needed to prevent neuronal death from ischemia (C) 2010 Elsevier Inc All rights reserved