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. 2012 Mar 15:5:33.
doi: 10.3389/fnmol.2012.00033. eCollection 2012.

AKT/GSK3 signaling pathway and schizophrenia

Effat S Emamian  1
Affiliations

AKT/GSK3 signaling pathway and schizophrenia

Effat S Emamian. Front Mol Neurosci. .

Abstract

Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3β in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms.

Keywords: AKT; GSK3; PKB; neuronal signaling; phosphorylation; schizophrenia.

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Figures

Figure 1
Figure 1
The AKT signaling pathway. AKT is activated by PI3K, which itself is activated by several upstream signaling pathways such as insulin receptors, receptor tyrosine kinases, G protein coupled receptors, cytokine receptors, etc. After activation, it targets several downstream molecules and change their activity by phosphorylation or complex formation. AKT is involved in cell proliferation, glucose metabolism, cell survival, cell cycle, protein synthesis, and in neuronal morphology and plasticity by regulation of several downstream molecules shown in this figure. AKT is involved in cell proliferation through interaction with a number of proteins involved in cell cycle, including Cyclin D1, p21Cip, p27Kip, Myt1, and Wee1. AKT also plays a crucial role in cell survival through interaction with Bad, MDM2 and the subsequent regulation of p53, FoxO1, Bcl-2, and Bax. AKT regulates glucose metabolism through regulation of GSK-3, PFKFB2, PIP5K, and AS160. It could also affect protein synthesis through interaction with S6 kinase, TSC1, and mTOR signaling. In more recent years, AKT's role in neurodegeneration was uncovered, mediated through phosphorylation of Huntingtin and Ataxin-1. AKT also has a role in synaptic plasticity, by phosphorylation of GABAA receptor. Pathway diagram reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).
See this image and copyright information in PMC

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