"Investigation of PI3K/Akt/GSK3/mTORC1 signaling pathway activity in patients with first psychotic episode"

Abstract

Schizophrenia is a chronic psychiatric disease characterized by changes in many genes interacting with a host of exogenous factors. An ongoing research goal is focused on biomarkers for categorization and prediction of disease progression and antipsychotic drug responses. In addition to classical biomarkers, studies approaching schizophrenia at the systems biology level have highlighted the role of signaling pathways. A central signaling pathway associated with schizophrenia is the Akt/GSK3/mTORC1 pathway. However, despite genetic and biological validation in chronic schizophrenia patient panels and preclinical animal models, whether Akt/GSK3/mTORC1 signalling is deregulated at an early clinical stage as in drug-naïve schizophrenia patients at the time of diagnosis is unknown.

In the present report, we have conducted a pilot study investigating Akt/GSK3/mTORC1 pathway activity in peripheral blood mononuclear cells (PBMCs) of patients with first psychotic episode (FEP). Thirty-seven patients were recruited using standard criteria, blood samples were obtained and PBMCs were isolated. Blood samples from healthy volunteers were processed in parallel. PBMCs protein extracts were prepared and processed for western blotting with antibodies against phosphorylated Akt, GSK3 and S6.

Our results indicate dysregulation of Akt, GSK3 and mTORC1 signalling activities in PBMCs from FEP patients compared to healthy controls. Mostly evident at the level of mTORC1 and ribosomal S6K, as phospho-S6 is significantly decreased in FEP patients (p<0.05, Mann-Whitney test).

These preliminary findings corroborate post-mortem studies showing decreased mTORC1 activity in chronic schizophrenia patients and further suggest that peripheral mTORC1 signalling is decreased in drug naïve FEP patients.

POLIZOU Alexandra