Converging evidence speak in favor of an abnormal susceptibility to oxidative stress in schizophrenia. A decreased level of glutathione (GSH), the principal non-protein antioxidant and redox regulator, was observed both in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. Moreover, patients have an abnormal GSH synthesis most likely of genetic origin: Two independent case- control studies showed a significant association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/ 7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease-associated genotypes correlated with a decrease in GCLC protein expression, GCL activity and GSH content. These results suggest that GSH synthesis dysfunction represent a vulnerability factor in schizophrenia. Such a redox dysregulation during development could underlie the structural and functional anomalies in connectivity: In experimental models, GSH deficit induces anomalies similar to those observed in patients.
(a) Morphology: decrease in normal spines in prefrontal pyramids and in GABA-parvalbumine but not of -calretinine immunoreactivity in anterior cingulate.
(b) Physiology: impairment of NMDA-dependant synaptic plasticity and of dopamine modulation of NMDA-induced Ca2+ response. (
c) Cognition: deficit in olfactory integration and in object recognition.
In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysfunction of GSH metabolism during development represent a major risk factor contributing to the disconnectivity syndrome in schizophrenia.