Increased Glycogen Synthase Kinase-3β mRNA Level in the Hippocampus of Patients with Major Depression: A Study Using the Stanley Neuropathology Consortium Integrative Database

Objective Glycogen synthase kinase-3β (GSK-3β) has become recognized as a broadly influential enzyme affecting diverse range of biological functions, including gene expression, cellular architecture, and apoptosis. The results of previous studies suggest that GSK-3β activity may be increased in the brain of patients with major depressive disorders (MDD). A recent animal study reported increased GSK-3β messenger ribonucleic acid (mRNA) level in the hippocampus of those with depression. However, few studies have investigated GSK-3β activity in the brain of patients with MDD. Methods In order to test whether patients with MDD have an increase in GSK-3β activity in the brain compared to normal controls, we explored GSK-3β expression level in all brain regions by using the Stanley Neuropathology Consortium Integrative Database (SNCID), which is a web-based method of integrating the Stanley Medical Research Institute data sets. Results The level of GSK-3β mRNA expression in the hippocampus was significantly increased in the MDD group (n=8) compared with the control group (n=12, p<0.05). Spearman's test also reveals that GSK-3β mRNA expression levels were significantly correlated with nitric oxide synthase 1 (NOS1)(ρ=0.70, p<0.0001) and stathmin-like 3 (STMN3)(ρ=0.70, p<0.0001) in the hippocampus. Conclusion Our results correspond with the results of previous animal studies that reported increased GSK-3β activity in the hippocampus of those with depression. Our findings also suggest that oxidative stress-induced neuronal cell death and abnormal synaptic plasticity in the hippocampus may play important roles in the pathophysiology of major depression.

[1]  M. Roh,et al.  In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. , 2004, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[2]  H. Manji,et al.  AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. , 2004, The international journal of neuropsychopharmacology.

[3]  S. Watson,et al.  Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia , 2004, Biological Psychiatry.

[4]  R. Jope,et al.  The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways , 2006, Progress in Neurobiology.

[5]  E. Kandel,et al.  stathmin, a Gene Enriched in the Amygdala, Controls Both Learned and Innate Fear , 2005, Cell.

[6]  G. Atweh,et al.  Role of stathmin in the regulation of the mitotic spindle: potential applications in cancer therapy. , 2002, The Mount Sinai journal of medicine, New York.

[7]  D. Melton,et al.  A molecular mechanism for the effect of lithium on development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Collier,et al.  Association study of the INPP1, 5HTT, BDNF, AP-2β and GSK-3β GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder , 2006, Neuroscience Letters.

[9]  D. Butterfield,et al.  Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity , 2007, Nature Reviews Neuroscience.

[10]  R. Yolken,et al.  The Stanley Foundation brain collection and Neuropathology Consortium , 2000, Schizophrenia Research.

[11]  D. Kimelman,et al.  Role of Glycogen Synthase Kinase-3β in Neuronal Apoptosis Induced by Trophic Withdrawal , 2000, The Journal of Neuroscience.

[12]  B. Ravnkilde,et al.  Hippocampal volume and depression: a meta-analysis of MRI studies. , 2004, The American journal of psychiatry.

[13]  S. Tsai,et al.  Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder , 2008, The Pharmacogenomics Journal.

[14]  M. Webster,et al.  Correlation analysis between genome-wide expression profiles and cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders , 2010, Molecular Psychiatry.

[15]  P. Cohen,et al.  Glycogen synthase kinase-3 from rabbit skeletal muscle. , 2005, Methods in enzymology.

[16]  Thomas E. Nichols,et al.  Association of GSK3beta polymorphisms with brain structural changes in major depressive disorder. , 2009, Archives of general psychiatry.

[17]  M. Roh,et al.  In Vivo Regulation of Glycogen Synthase Kinase-3β (GSK3β) by Serotonergic Activity in Mouse Brain , 2004, Neuropsychopharmacology.

[18]  M. Webster,et al.  Postmortem brain tissue for drug discovery in psychiatric research. , 2009, Schizophrenia bulletin.

[19]  N. Sousa,et al.  Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: The role of glycogen-synthase-kinase-3β , 2008, Neuroscience.

[20]  C. Chiueh,et al.  Preconditioning regulation of bcl‐2 and p66shc by human NOS1 enhances tolerance to oxidative stress , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  A. Malafosse,et al.  Alteration in Kinase Activity But Not in Protein Levels of Protein Kinase B and Glycogen Synthase Kinase-3β in Ventral Prefrontal Cortex of Depressed Suicide Victims , 2007, Biological Psychiatry.

[22]  Abraham Weizman,et al.  Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on β-catenin in mouse hippocampus , 2004, Biological Psychiatry.

[23]  F. Guimarães,et al.  Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. , 2008, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[24]  H. Eldar-Finkelman,et al.  Role of glycogen synthase kinase-3β  in early depressive behavior induced by mild traumatic brain injury , 2007, Molecular and Cellular Neuroscience.

[25]  P. Cohen,et al.  Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. , 1980, European journal of biochemistry.

[26]  Bin Wang,et al.  Neuronal nitric oxide synthase contributes to chronic stress‐induced depression by suppressing hippocampal neurogenesis , 2007, Journal of neurochemistry.