Abstract
Recent studies have shown that microRNAs (miRNAs) play a role as regulators of neurodevelopment by modulating gene expression. Altered miRNA expression has been reported in various psychiatric disorders, including schizophrenia. However, the changes in the miRNA expression profile that occur during the initial stage of schizophrenia have not been fully investigated. To explore the global alterations in miRNA expression profiles that may be associated with the onset of schizophrenia, we first profiled miRNA expression in plasma from 17 patients with first-episode schizophrenia and 17 healthy controls using microarray analysis. Among the miRNAs that showed robust changes, the elevated expression of has-miR-223-3p (miR-223) was validated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using another independent sample set of 21 schizophrenia patients and 21 controls. To identify the putative targets of miR-223, we conducted a genome-wide gene expression analysis in neuronally differentiated SK-N-SH cells with stable miR-223 overexpression and an in silico analysis. We found that the mRNA expression levels of four genes related to the cytoskeleton or cell migration were significantly downregulated in miR-223-overexpressing cells, possibly due to interactions with miR-223. The in silico analysis suggested the presence of miR-223 target sites in these four genes. Lastly, a luciferase assay confirmed that miR-223 directly interacted with the 3′ untranslated regions (UTRs) of all four genes. Our results reveal an increase in miR-223 in plasma during both the first episode and the later stage of schizophrenia, which may affect the expression of cell migration-related genes targeted by miR-223.
Highlights
Schizophrenia is one of the most common mental disorders, affecting ~1% of the worldwide population
Identification of the plasma miRNA signature To investigate the possible involvement of plasma miRNAs in the initial stage of schizophrenia, the global miRNA expression in plasma was determined by 3D-Gene Human miRNA Oligo Chips from 17 patients with first-episode schizophrenia (FES) and 17 healthy controls
Our results revealed that the luciferase activities of the wild-type INPP5B, Ras homolog family member B (RHOB), SKI-like protooncogene (SKIL), and SYNE1 3′ untranslated regions (UTRs) luciferase reporters were significantly attenuated in SK-N-SH cells cotransfected with miR-223 compared to SK-N-SH cells cotransfected with a scrambled control
Summary
Schizophrenia is one of the most common mental disorders, affecting ~1% of the worldwide population. The onset of this disease often occurs during adolescence, and the subsequent chronic course of the illness can become a heavy burden and a serious public health issue[1]. Other studies have reported that circulating miRNAs, which were detected in several body fluids, including serum, plasma, and cerebrospinal fluid, are influenced by the pathological conditions of many psychiatric disorders, including schizophrenia[19,20,21,22]. Despite the accumulating evidence described above, the changes in plasma miRNA levels that occur at the initial stage of schizophrenia have not been fully explored
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