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.