Domoic acid (DomA) is a potent marine neurotoxin. By activating α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid/kainate receptors, DomA induces oxidative stress-mediated apoptotic cell death in neurons. The effect of prolonged (10 days) exposure to a low, nontoxic concentration (5nM) of DomA on acute (intermediate concentration) neurotoxicity of this toxin was investigated in cerebellar granule neurons (CGNs) from wild-type mice and mice lacking the glutamate cysteine ligase (GCL) modifier subunit (Gclm (/)). CGNs from Gclm (/) mice have very low glutathione (GSH) levels and are very sensitive to DomA toxicity. In CGNs from wild-type mice, prolonged exposure to 5nM DomA did not cause any overt toxicity but reduced oxidative stress-mediated apoptotic cell death induced by exposure to an intermediate concentration (100nM for 24h) of DomA. This protection was not observed in CGNs from Gclm (/) mice. Prolonged DomA exposure increased GSH levels in CGNs of wild-type but not Gclm (/) mice. Levels of GCLC (the catalytic subunit of GCL) protein and mRNA were increased in CGNs of both mouse strains, whereas levels of GCLM protein and mRNA, activity of GCL, and levels of GCL holoenzyme were only increased in CGNs of wild-type mice. Chronic DomA exposure also protected wild-type CGNs from acute toxicity of other oxidants. The results indicate that CGNs from Gclm (/) mice, which are already more sensitive to DomA toxicity, are unable to upregulate their GSH levels. As Gclm (/) mice may represent a model for a common human polymorphism in GCLM, such individuals may be at particular risk for DomA-induced neurotoxicity.