Low GSK-3beta in schizophrenia as a consequence of neurodevelopmental insult

Glycogen synthase kinase-3 (GSK-3) is a protein kinase highly abundant in brain and involved in signal transduction cascades, particularly neurodevelopment. Its activity and protein levels have been reported to be over 40% lower in postmortem frontal cortex of schizophrenic patients. GSK-3beta in occipital cortex of schizophrenic patients was not reduced, suggesting regional specificity. There was no reduction in GSK-3beta protein levels in fresh and immortalized lymphocytes and both GSK-3 activity and GSK-3beta mRNA levels in fresh lymphocytes from schizophrenic patients. In the schizophrenia-related neonatal ventral hippocampal lesion rat model, we measured GSK-3beta protein levels and GSK-3 activity in the frontal cortex. GSK-3beta protein levels in lesioned rats were significantly lower than in sham rats, favoring perinatal insult as a cause of low GSK-3beta in schizophrenia. Taken together, these studies suggest that low GSK-3 in postmortem brain of schizophrenic patients is a late consequence of perinatal neurodevelopmental insult in schizophrenia. In rats, acute or chronic cold restraint stress did not change GSK-3beta protein levels. Chronic treatment of rats with lithium, valproate, haloperidol or clozapine did not change rat cortical GSK-3beta protein levels ex vivo, supporting the concept that low GSK-3beta in schizophrenia is not secondary to stress or drug treatment. Our initial findings of low GSK-3beta protein levels in postmortem brain have been replicated by another group. Our own group has found additionally that GSK-3beta mRNA levels were 40% lower in postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients, supporting our previous findings. Further studies will be aimed at determining whether nonspecific neonatal damage or only specific factors cause low GSK-3 as a late effect. We plan to study whether low GSK-3beta activity is associated with biochemical effects such as elevated beta-catenin levels.