Genetic overlap between schizophrenia and bipolar disorder: a study with AKT1 gene variants and clinical phenotypes.

INTRODUCTION: A number of epidemiological and genetic studies suggests an overlap of Schizophrenia and Bipolar disorder across the traditional binary classification. AKT1 gene variants were previously shown to be associated with schizophrenia. In this study, our aim was to determine whether AKT1 gene variants are associated with particular phenotypes for schizophrenia (SCZ) and bipolar disorder (BPD). METHODS: This study included 529 subjects of European ancestry: 364 patients suffering from SCZ, BPD or schizoaffective disorder and 165 healthy controls. BPD patients were additionally subdivided into two groups: BPD with or without psychosis. Six AKT1 variants were assessed in a case-control study and allelic associations were analyzed. Moreover, meta-analyses were performed for those variants found in case-control studies of schizophrenia and schizoaffective disorder. RESULTS: Nominal associations were found for three AKT1 gene variants, namely rs3803300, rs2494732 and rs2498804, in the four phenotypes. Two SNP survived Bonferroni corrections for multiple testing: rs3803300 (p<0.001) and rs2498804 (p<0.03) in group 1 (BPD without psychosis). In group 2 (BPD with psychosis) and in group 4 (SCZ), rs3803300 was significant but did not survive multiple testing. While rs2494732 was associated with the presence of psychosis (group-2, 3 and 4), rs2498804 was associated with affective symptoms (groups-1, 2 and 3). One meta-analysis found a significant level of association between rs3803300 and schizophrenia in Asian subjects. CONCLUSION: AKT1 gene variations appeared to impact the risk for a class of psychiatric symptoms, comprising SCZ and BPD. Our findings support the view that AKT1 genetic variants are shared by both BPD and SCZ.

Protein levels of ß-catenin and activation state of glycogen synthase kinase-3ß in major depression. A study with postmortem prefrontal cortex.

BACKGROUND: The Wnt/GSK3ß signaling pathway was implicated in mood disorders. Beta-catenin is a protein targeted by this signaling axis. We aimed to examine whether there is an abnormality in this signaling axis in major depression. METHODS: Postmortem brains from 20 depressed and 20 non-depressed subjects were used. In both groups, suicide and non-suicide were included in equal number. Protein levels of ß-catenin, tGSK3ß and ser(9)-pGSK3ß were determined in prefrontal cortex. RESULTS: ANOVA yielded significant variations between groups in ß-catenin (F(3,36)=19.5; p<0.001) and pGSK3ß protein (F(3,36)=14.3; p<0.001) and in tGSK3ß-to-pGSK3ß ratio (F(3,36)=10.9; p<0.001). Fisher tests showed decrease in both groups of MDD and MDD with suicide (MDD+S) for ß-catenin (p<0.001) and pGSK3ß levels (p<0.001) respectively. The tGSK3ß-to-pGSK3ß ratio was increased in MDD and MDD+S subjects (p<0.001). A negative correlation was observed between ß-catenin levels and the activation state of the GSK3ß (r2=0.358; p<0.005). LIMITATIONS: The sample was small and only a fraction of s(9)-pGSK3ß, albeit significant, was used and; the mood state at the time of death was unknown. CONCLUSIONS: The study observed a dysregulation of Wnt/GSK3ß signaling associated with a lifetime of major depression. The study may have relevance in further development of drugs based on GSK3ß inhibition.

Alterations in phosphatidylinositol 3-kinase activity and PTEN phosphatase in the prefrontal cortex of depressed suicide victims.

BACKGROUND: Recent studies have reported alterations in protein kinase B (PKB)/Akt and in its downstream target, glycogen synthase kinase 3ß, in depression and suicide. The aim of the present study was to investigate possible impairment of the upstream regulators, namely phosphatidylinositol 3-kinase (PI3K) and PTEN. METHODS: The ventral prefrontal cortex (Brodmann's area 11) of 24 suicide victims and 24 drug-free nonsuicide subjects was used. The antemortem diagnoses of major depression disorder were obtained from the institutional records or psychological autopsy, and toxicological analyses were performed. Protein levels of PI3K and PTEN were assayed using the immunoblot method, and the kinase activity of PI3K and Akt was determined by phosphorylation of specific substrates. RESULTS: A decrease was observed in the enzymatic activity of PI3K [ANOVA: F(3, 44) = 9.20; p < 0.001] and Akt1 [ANOVA: F(3, 44) = 13.59; p < 0.001], without any change in protein levels, in both depressed suicide victims and depressed nonsuicide subjects (p < 0.01 and p < 0.002, respectively). PTEN protein levels were increased in the same groups [ANOVA: F(3, 44) = 10.5; p < 0.001]. No change was observed in nondepressed suicide victims. CONCLUSION: This study concludes that attenuation of kinase activity of PKB/Akt in depressed suicide victims may be due to the combined dysregulation of PTEN and PI3K resulting in insufficient phosphorylation of lipid second messengers. The effect is associated with major depression rather than with suicide per se. Given the cellular deficits reported in major depression, the study of enzymes involved in cell survival and neuroplasticity is particularly relevant to neurotrophic factor dysregulation in depression.

Early effects of mood stabilizers on the Akt/GSK-3beta signaling pathway and on cell survival and proliferation.

RATIONALE: Lithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed. OBJECTIVES: We evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3beta axis, this pathway was explored for other drugs. MATERIALS AND METHODS: The SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3beta mRNA and protein were assessed for the seven drugs as well. RESULTS: Lithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3beta phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3beta, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3beta axis. CONCLUSION: Valproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3beta axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis.

Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims.

BACKGROUND: Past studies in the neurobiology of suicide have reported alterations in serotonin and downstream effectors, such as Akt/protein kinase B. In this study, we aimed to examine possible abnormality in the Akt/glycogen synthase kinase-3beta (GSK-3beta) axis of depressed suicide victims' brains. METHODS: Twenty suicide victims and 20 drug-free non-suicide subjects were included for a postmortem study. The ventral prefrontal cortex area (BA'11) was used, and antemortem diagnoses of major depression disorder (MDD) (DSM-IV) were made from Institution's records. The protein levels of GSK-3alpha/beta and Akt-1 were assayed with the Western blot method, and the kinase activity of Akt and GSK-3alpha/beta were determined by phosphorylation of specific substrates. RESULTS: There was no change either in GSK-3alpha/beta and Akt-1 protein levels or in lithium-inhibitable total GSK-3alpha/beta enzyme activity of the ventral prefrontal cortex. The enzyme activity of Akt decreased significantly [analysis of variance (ANOVA): F(3,36)=5.372; p= .003], whereas GSK-3beta activity increased significantly [ANOVA: F(3,36)=8.567; p= .002] in depressed suicide victims and non-suicide subjects but not in non-depressed suicide victims. CONCLUSIONS: This study indicated that the activity rather than the protein levels of Akt and GSK-3beta was altered. The alteration was associated with MDD rather than with suicide per se.