Converging evidence speak in favor of an abnormal susceptibility to oxidative stress in schizophrenia. It is however unclear if this is a primary cause, due to a defect of the redox regulation system, or a secondary effect due to unknown processes including excessive production of reactive oxygen species. We previously reported in schizophrenia patients a decreased level of glutathione (GSH), the principal non-protein antioxidant and redox regulator, both in cerebrospinal- fluid and prefrontal cortex. To identify possible genetic causation, we studied genes involved in GSH metabolism. Case-control association study of single nucleotide polymorphisms (SNP) from the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) modifier subunit (GCLM) was performed in two populations: Swiss (patients/ controls: 40/31) and Danish (349/348)(Tosic&al AmJHumGen06). We found a strong association of SNP rs2301022 in the 5' region of GCLM gene (Danish: c2 = 13.2, p=0.023 after correction for multiple testing). Evidence for GCLM as a risk factor was confirmed in linkage study of NIMH families. Moreover, we observed a decrease in GCLM mRNA levels in patient fibroblasts and they showed a significant correlation with the associated SNP. Interestingly, Dalton and al reported in GCLM knock-out mice an increased feedback inhibition of GCL activity, resulting in 60% decrease of brain [GSH], a situation analogous to patients. These mice exhibited an increased sensitivity to oxidative stress. Similar- ly, under oxidative stress conditions, GCL enzymatic activity was also decreased in patient fibroblasts. In an animal model with GSH deficit we observed a decreased number of dendritic spines in pyramidal cells and an abnormal development of parvalbumine immunoreactive GABA neurons in prefrontal cortex similar to those reported in patient. In addition, GSH depletion in hippocampal slices impairs long term potentiation and as such may be implied in cognitive disturbances. These results on the genetic and functional anomalies in GSH synthesis, combined with observations that GSH deficient models reveal morphological (GABA interneurones), electrophysiological (NMDA hypofunction), and behavioral (cognitive functions) anomalies analogous to those observed in patients, suggest that GCLM allelic variant is a vulnerability factor for schizophrenia. This may represent, among other factors, one primary, causal mechanism leading to redox dysregulation and oxidative stress in schizophrenia.