Abstract
BackgroundThe mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. This study aimed to examine the expression of mTOR pathway genes in patients with schizophrenia treated with olanzapine, which is considered an mTOR inhibitor and autophagy inducer.MethodsThirty-two patients with acute schizophrenia who had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d) and 32 healthy volunteers were recruited. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of patients with schizophrenia, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RAPTOR, and DEPTOR, were detected in fasting venous blood samples from all subjects using real-time quantitative PCR.ResultsThe MTOR and RICTOR mRNA expression levels in patients with acute schizophrenia were significantly decreased compared with those of healthy controls and further significantly decreased after four weeks of olanzapine treatment. The DEPTOR mRNA expression levels in patients with acute schizophrenia were not significantly different from those of healthy controls but were significantly increased after treatment. The expression levels of the RAPTOR mRNA were not significantly different among the three groups. The pairwise correlations of MTOR, DEPTOR, RAPTOR, and RICTOR mRNA expression levels in patients with acute schizophrenia and healthy controls were significant. After olanzapine treatment, the correlations between the expression levels of the DEPTOR and MTOR mRNAs and between the DEPTOR and RICTOR mRNAs disappeared.ConclusionsAbnormalities in the mTOR pathway, especially DEPTOR and mTORC2, might play important roles in the autophagy mechanism underlying the pathophysiology of schizophrenia and effects of olanzapine treatment.
Highlights
The mammalian target of rapamycin protein signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment
MTOR is a highly conserved serine/threonine kinase with a molecular weight of 289 kDa [3]. mTOR, regulatoryassociated protein of mTOR (RAPTOR), and DEP domaincontaining MTOR-interacting protein (DEPTOR) form the mechanistic target of rapamycin complex 1 (mTORC1) complex, which is mainly involved in cell growth, apoptosis, energy metabolism, and autophagy; mTOR, DEP domain-containing MTOR-interacting protein (DEPTOR), and rapamycin-insensitive companion of mTOR (RICTOR) form the mTORC2 complex, which is mainly involved in the construction and maintenance of cytoskeletal proteins [4]
In the present study, the mRNA expression levels of MTOR, RAPTOR, and RICTOR were significantly lower in the case group before olanzapine treatment than in the control group, while DEPTOR mRNA expression levels showed no significant difference between the two groups
Summary
The mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. Recent research has indicated that the mammalian target of rapamycin protein (mTOR) pathway may be involved in schizophrenia pathogenesis [2]. The major effector target proteins of the mTOR downstream pathway are 4E-BP1 and S6K1, which are involved in protein translation initiation, gene transcription, and cell cycle regulation [5]. MTOR mainly regulates the rate-limiting step in the initial local translation of a particular gene upon synaptic activation and induces de novo dendritic protein synthesis, which allows the long-term maintenance of functional changes in the synapse [6,7,8]. Lin et al reported that elevated mTORC1-S6K1 (ribosomal S6 kinase 1, S6K1) signaling occludes dynamic DRD1 signaling downstream of DARPP-32 (protein phosphatase 1, regulatory inhibitor subunit 1B) and blocks multiple DRD1 responses, including dynamic gene expression, DRD1dependent corticostriatal plasticity, and DRD1 behavioral responses, such as sociability, while the levels of candidate biomarkers of mTORC1-DARPP-32 occlusion are increased in the brains of human subjects with a disease in association with elevated mTORC1-S6K1 levels [12]
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