GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients

The protein kinase glycogen synthase kinase-3 (GSK-3) is highly abundant in brain and involved in signal transduction cascades, particularly during neurodevelopment. We have previously found reduced GSK-3β mRNA levels, protein levels and GSK-3 total (α+β isoforms) activity in postmortem frontal cortex of schizophrenic patients in the Stanley Medical Research Institute's Brain Collection. To verify and extend these findings, GSK-3 parameters were now measured in the frontal cortex (BA9) and hippocampus obtained from the Rebecca L. Cooper Research Laboratories postmortem brain collection. Fifteen pairs of schizophrenic patients and matched control subjects have been studied. No significant differences in GSK-3α and GSK-3β mRNA levels, GSK-3β protein levels or total GSK-3 (α+β) activity were found in the frontal cortex of the two diagnostic groups. Hippocampal GSK-3α and GSK-3β mRNA levels were significantly lower (22% and 28%, respectively) in the tissue from the schizophrenic patients compared with the normal controls. Hippocampal GSK-3β protein levels in the schizophrenic patients were 24% significantly lower than control values only after omission of three outlier subjects. Hippocampal total GSK-3 (α+β) activity in the patients was 31% lower in the schizophrenic patients vs. control subjects. This difference was marginally significant. While our previous data on GSK-3β in postmortem brain and the recent report that there is impaired AKT1-GSK-3β signaling in schizophrenia suggest that changes in pathways involving protein kinases such as AKT1 and GSK-3β in schizophrenia are complex, our present data do not provide strong evidence in support of the involvement of GSK-3β in schizophrenia. Therefore, further investigation in a greater number of brain samples is warranted to better clarify the possible role of this enzyme in the pathophysiology of schizophrenia.