Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia

Abstract

Alterations in intracellular signaling pathways are important in treating complex neuropsychiatric disorders 1 . Signaling pathway components, including several protein kinases and phosphatases, are direct targets of some of the most effective medications for treating these disorders. For example, lithium, one of the most established treatments for bipolar disorder (BPD), is believed to exert its therapeutic effects by directly modulating the activity of inositol monophosphatase and of glycogen synthase kinase 3β (GSK3β) 1 . It is still unclear, however, whether abnormalities in signaling pathways are central to the pathophysiology of psychiatric illnesses, including schizophrenia. Nevertheless, genes regulating such signaling cascades, especially those affecting synaptic transmission and plasticity, are good candidate susceptibility genes. RESULTS Low levels of AKT1 in individuals with schizophreniaIt is well established that most of the central nervous system (CNS) protein kinases and phosphatases are involved in a wide variety of cellular functions and are expressed in diverse cell types including peripheral blood lymphocytes. We speculated that alterations in brain levels or activity of protein kinases and phosphatases may contribute to schizophrenia susceptibility in humans and that this might be observed in the peripheral tissues of individuals with schizophrenia. We examined the abundance of several kinases implicated in synaptic plasticity (PRKACA, AKT1, PRKC, MAP3K, GSK3β, PIK3CB and PIK3R2) 2-4 . We assessed changes in protein levels because they are more likely to be cell-autonomous and less likely to be influenced by the cellular environment when compared, for example, with rapid and reversible activity modifications through phosphorylation. Protein extracts from lymphocyte-derived cell lines from individuals with schizophrenia (n = 28) and unaffected controls (n = 28) were subjected to SDS-PAGE and immunoblot analysis. Levels of protein kinase AKT1 were 68% lower in individuals with schizophrenia than in controls (Fig. 1a, P = 0.014, Mann-Whitney test, corrected for eight tests). In contrast, we observed no differences in the levels of the other kinases tested.This initial exploratory analysis may have been confounded by an imperfect match of cases and controls and the influence of Epstein-Barr virus (EBV) transformation on the levels of AKT1. Nonetheless, the specificity of our findings together with the fact that the same cellular pathway has been implicated in mood disorders 1 prompted us to follow up our initial observation using four complementary approaches. First, we attempted to verify a reduction in AKT1 levels in postmortem frontal cortex, one of the primary sites of disease pathology. Second, we examined whether the reduction in AKT1 levels was reflected by a reduction in substrate phosphorylation in both peripheral lymphocytes and postmortem frontal cortex. Third, we tested whether certain variants of the gene encoding AKT1 were preferentially transmitted in individuals with schizophreni...

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

“…Additionally, we probed all blots for b-Tubulin, which was used as internal lane loading control. b-Tubulin has previously been used as internal control 52,53 and several studies have found expression of b-Tubulin to be unaffected in schizophrenic brain. 54,55 However, in order to further minimize the potential effect of dendritic loss on bTubulin expression, we used an antibody that recognizes not only the neuron-specific isoform III, but all b-Tubulin isoforms (I, II, III, IVa and IVb), representing both neuronal and non-neuronal tubulin expression.…”

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

“…Akt is a serine/threonine kinase that regulates cell growth, glucose uptake, metabolism, and increases cell survival. A reduction in Akt levels in the frontal cortex and hippocampus of schizophrenic patients (Emamian et al, 2004) may be connected with neurodegenerative changes observed in this illness. Activated Akt phosphorylates many intracellular substrates, for example, it phosphorylates the GSK-3b at Ser9 and inactivates it.…”

The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia

“…17,20 Several researches have reported that abnormalities of neural cell adhesion, neuronal function, and Wnt/Wingless exist in schizophrenia. [10][11][12][13][14][15]18,19,[23][24][25][26] Third, APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. 27,28 Three SNPs of APC are associated with schizophrenia.…”

“…9 Recently, evidences for potential disturbances of Wnt signaling pathways in schizophrenia have accumulated. [10][11][12][13][14][15] However, as far as the authors are aware, the involvement of APC in schizophrenia has not been reported. The immunoprecipitation experiment results suggested that APC is involved in cell adhesion.…”