Peripheral Blood Of Schizophrenia Patients Research Articles

Peripheral Blood Non-Coding RNA as Biomarker for Schizophrenia: A Review.

Schizophrenia (SCZ) is a complex and heterogeneous neuropsychiatric disorder that lacks objective diagnostic indicators and the pathogenesis remain unclear. Genetic factors may exert a significant impact on the development of the condition. While obtaining brain tissue for biopsy in the course of adjuvant diagnosis of SCZ patients may not be possible, the collection of peripheral blood is more accessible and easier to implement. In recent years, the development and application of RNA sequencing technology has made seeking biomarkers of SCZ becomes more feasible. There is emerging evidence suggesting that certain non-coding RNAs (ncRNA) are distinctly different in the peripheral blood of SCZ patients and healthy controls. Although the mechanisms remain unclear, these aberrantly expressed ncRNAs may be intimately associated with the onset and development of SCZ and may be of great significance for the diagnosis and treatment of SCZ. Therefore, we reviewed the expression of distinct types of ncRNAs that have been found in the peripheral blood of SCZ patients and explored their potential application as diagnostic biomarkers of SCZ. Differentially expressed ncRNAs in the peripheral blood of SCZ patients could not only serve as potential diagnostic biomarkers and therapeutic targets for SCZ but may also have implications for advancing understanding of the molecular mechanisms underlying the development of SCZ and elucidating the complex etiology of SCZ. Early diagnostic biomarkers obtained directly from peripheral blood are of great significance for the timely diagnosis and treatment of SCZ. Our review will enhance the comprehension of molecular mechanisms of SCZ and contribute to the identification of promising ncRNAs in peripheral blood for both diagnosis and therapy of SCZ.

An analysis of POMC gene methylation and expression in patients with schizophrenia.

Schizophrenia is a chronic mental disorder that affects millions of people and is believed to be caused by both environmental and genetic factors. Despite extensive research, the exact mechanisms underlying schizophrenia are still unclear. Studies have shown that numerous psychiatric disorders are associated with methylation of the POMC gene, which encodes adrenocorticotropic hormone, a critical player in the hypothalamic-pituitary-adrenal axis. However, the association between DNA methylation in POMC patients and schizophrenia remains unclear. In this study, we evaluated three fragments of the POMC promoter region, including 51 CpG sites, in the peripheral blood of schizophrenia patients and healthy controls. The POMC protein level was measured via enzyme-linked immunosorbent assay (ELISA). The schizophrenia group exhibited significantly greater levels of methylation of the POMC gene than those in the control group. The methylation level of the POMC-2 fragment was significantly greater in the patient group than in the control group. There were 17 significantly hypermethylated CpG sites in the patient group. After stratification by sex, POMC methylation levels were found to be significantly greater in male schizophrenia patients than in healthy controls; the methylation levels of POMC-2 fragments were greater in the male patient group; nine CpG sites were significantly hypermethylated in the male patient group; and only one CpG site was significantly hypermethylated in the female patient group. The POMC protein level in patients was significantly lower than that in healthy controls. These findings demonstrate that the DNA methylation of POMC might be associated with the pathophysiology of schizophrenia. Overall, studying the correlation between POMC methylation and schizophrenia may contribute to the diagnosis and evaluation of neuropsychiatric disorders.

MiR-9-5p deficiency contributes to schizophrenia

MicroRNA-9-5p (miR-9-5p) is highly expressed in the brain and has been implicated in the risk of schizophrenia. We compared the expression levels of miR-9-5p in schizophrenia cases and healthy controls and evaluated whether regulatory targets of miR-9-5p are enriched in schizophrenia genome-wide risk genes. Literature-based analysis was conducted to construct molecular pathways connecting miR-9-5p and schizophrenia. We found that the expression levels of miR-9-5p were down-regulated in the peripheral blood of schizophrenia patients compared with those in healthy controls. miR-9-5p can regulate 24 out of the 1136 genome-wide risk genes of schizophrenia, which was higher than by chance (hypergeometric test P = 4.09E−06). The literature-based analysis showed that quantitative genetic changes driven by miR-9 exert more inhibitory (the IL1B, ABCB1, FGFR1 genes) than promoting (the INS gene) effects on schizophrenia, suggesting that miR-9 may protect against schizophrenia. Our results suggest that miR-9-5p deficiency may contribute to the development of schizophrenia.

Inhibition of MicroRNA-182/183 Cluster Ameliorates Schizophrenia by Activating the Axon Guidance Pathway and Upregulating DCC

Schizophrenia (SZ) is a complex disorder caused by a variety of genetic and environmental factors. Mounting evidence suggests the involvement of microRNAs (miRNAs) in the pathology of SZ. Accordingly, the current study set out to investigate the possible implication of the miR-182/183 cluster, as well as its associated mechanism in the progression of SZ. Firstly, rat models of SZ were established by intraperitoneal injection of MK-801. Moreover, rat primary hippocampal neurons were exposed to MK-801 to simulate injury of hippocampal neurons. The expression of miR-182/183 or its putative target gene DCC was manipulated to examine their effects on SZ in vitro and in vivo. It was found that miR-182 and miR-183 were both highly expressed in peripheral blood of SZ patients and hippocampal tissues of SZ rats. In addition, the miR-182/183 cluster could target DDC and downregulate the expression of DDC. On the other hand, inhibition of the miR-182/183 cluster ameliorated SZ, as evidenced by elevated serum levels of NGF and BDNF, along with reductions in spontaneous activity, serum GFAP levels, and hippocampal neuronal apoptosis. Additionally, DCC was found to activate the axon guiding pathway and influence synaptic activity in hippocampal neurons. Collectively, our findings highlighted that inhibition of the miR-182/183 cluster could potentially attenuate SZ through DCC-dependent activation of the axon guidance pathway. Furthermore, inhibition of the miR-182/183 cluster may represent a potential target for the SZ treatment.

Deregulatory miRNA-BDNF Network Inferred from Dynamic Expression Changes in Schizophrenia.

(1) Background: Brain-derived neurotrophic factor (BDNF) is one of the promising risk genes for schizophrenia (SZ), a disease with prominent dysregulation of miRNA networks. Here, we present a study of miRNA-BDNF co-expression changes in peripheral blood of SZ patients. (2) Methods: The expression levels of the BDNF mRNA and three validated binding miRNAs—miR-124-3p, miR-132-3p, and miR-206—were quantified in the blood of 48 healthy controls and 32 SZ patients before and after 12 weeks of treatment. The co-expression patterns were evaluated in the three groups. (3) Results: The expression levels of BDNF were significantly downregulated in SZ patients compared to the controls. After the treatment, the expression levels of BDNF were upregulated, while the expression levels of the three miRNAs were downregulated. Co-expression analyses showed positive correlations of this network in the SZ patients, while weak negative correlations were observed in the healthy controls. After the 12-week treatment, the overall correlation between BDNF and the three miRNAs reached the levels comparable to the healthy controls. (4) Conclusions: Our findings suggest the involvement of the miRNA-BDNF network in the onset and treatment of SZ.

Sex-dependent DNA hypermethylation of SLC6A4 in patients with schizophrenia

Schizophrenia (SCZ) is a mental health condition with a complex pathogenic mechanism. One important hypothesis of SCZ pathology is serotonin (5-HT) impairment, and the 5-HT transporter, encoded by the SLC6A4 gene, plays a key role in regulating 5-HT levels. Some studies have confirmed that the CpG island upstream of exon 1 and the island shore region of SLC6A4 are hypermethylated in SCZ; however, to the best of our knowledge, there has been no study on the methylation level of CpG islands downstream of SLC6A4 exon 1. Methylation of CpG islands downstream of SLC6A4 exon 1 was measured in the peripheral blood of SCZ patients with positive symptoms using the MethylTarget method. Overall, the methylation level of SLC6A4 was significantly higher in women than in men. In intergroup comparisons, the level of SLC6A4 methylation was higher in the SCZ group than in the control group, especially within the male subgroup. Moreover, methylation levels of several CpG sites correlated significantly with SCZ. These results suggest that epigenetic alterations of SLC6A4 are related to SCZ pathophysiology. These findings improve the current understanding of the role of the 5-HT system in the pathological development of SCZ.

Oxidative stress and schizophrenia: A comparative cross‐sectional study of multiple oxidative markers in patients and their first‐degree relatives

Schizophrenia (SCZ) is a chronic, disruptive mental disorder with unknown pathogenic mechanisms. Several studies evidenced that oxidative stress (OS) may be one of the causal factors to play a role in the pathophysiology of the disease. Our study aims to contribute to the SCZ research by investigating a possible relationship between the severity of illness (scored with "The Positive and Negative Syndrome Scale [PANSS]") and OS biomarkers in patients. We additionally assess the "first-degree-relatives (FDRs)" oxidative status with multiple parameters to test the idea of oxidative imbalance leads to disease progression as a genetical susceptibility factor. This study included: 50 adult patients with SCZ, 50 unaffected FDRs, and 50 controls. OS biomarkers included myeloperoxidase (MPO), total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), native thiol (NT). Photometric methods were used to measure the parameters in the peripheral blood samples of participants. Disulphide (DS) and oxidative stress index (OSI) parameters were calculated. TOS, DS, OSI levels were significantly higher, and TAS, TT, NT levels were significantly lower in both SCZ and FDRs than controls. In the SCZ group, MPO activity was significantly higher compared with other groups. Results in this study did not provide a strong correlation between the PANSS and selected biomarkers. There was a slightly negative correlation between TT and PANSS in the SCZ group (P=.041, r=-.297). OS biomarkers increased significantly in the peripheral blood of SCZ patients compared with other groups indicates the presence of OS in the aetiology of the disease. Mid-levels of oxidative markers found in FDRs imply that unaffected first-degree relatives have an increased risk for turning up to the clinical presentation stage.

Clinical evidence that a dysregulated master neural network modulator may aid in diagnosing schizophrenia

There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2's activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients <40 y old, we observed that nonphosphorylated CRMP2 was higher than in controls, while phosphorylated CRMP2 remained unchanged from control. In the brain, these changes were associated with dendritic structural abnormalities. The abundance of active CRMP2 with insufficient opposing inactive p-CRMP2 yielded a unique lowering of the p-CRMP2:CRMP2 ratio in SCZ patients, implying a disruption in the normal equilibrium between active and inactive CRMP2. These clinical data suggest that measuring CRMP2 and p-CRMP2 in peripheral blood might reflect intracerebral processes and suggest a rapid, minimally invasive, sensitive, and specific adjunctive diagnostic aid for early SCZ: increased CRMP2 or a decreased p-CRMP2:CRMP2 ratio may help cinch the diagnosis in a newly presenting young patient suspected of SCZ (versus such mimics as mania in bipolar disorder, where the ratio is high).

Exploring the mRNA expression level of RELN in peripheral blood of schizophrenia patients before and after antipsychotic treatment

BackgroundThe Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR.ResultsThe expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group.ConclusionThe up-regulation of RELN mRNA expression was current in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.

MiR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells

MicroRNAs (miRNAs) have been investigated in neurodevelopmental and psychiatric disorders including schizophrenia (SZ). Previous studies showed miRNAs dysregulation in postmortem brain tissues and peripheral blood of SZ patients. These suggest that miRNAs may play a role in the pathophysiology of SZ and be a potential biomarker of SZ. Previous studies also showed that miRNAs regulated neurogenesis and that neurogenesis was involved in the pathophysiology of SZ. In addition, a recent study showed that miR-19a and 19b, enriched in neural progenitor cells (NPC) in adult hippocampus, were increased in human NPC derived from induced pluripotent stem cell derived from SZ patients. However, it remains unclear whether the levels of miR-19a and 19b are altered in peripheral blood of SZ patients and how miR-19a and 19b affects neurogenesis. To elucidate them, first we examined the levels of miR-19a and 19b in peripheral blood of SZ patients with quantitative RT-PCR and showed that the level of miR-19b, but not miR-19a, was significantly higher (miR-19a: p = 0.5733, miR-19b: p = 0.0038) in peripheral blood of SZ patients (N = 22) than that of healthy controls (N = 19). Next, we examined the involvement of miR-19b in proliferation and survival of mouse neonatal mice hippocampus-derived NPC with BrdU assay and TUNEL assay. The silencing of miR-19b significantly increased proliferation (N = 5, p = 0.0139), but not survival (N = 5, p = 0.9571), of neonatal mice hippocampus-derived NPC. These results suggest that the level of miR-19b in peripheral blood is a potential biomarker of schizophrenia and that the higher level of miR-19b may increase the vulnerability of SZ via attenuating proliferation of hippocampal NPC.

Profiling haplotype specific CpG and CpH methylation within a schizophrenia GWAS locus on chromosome 14 in schizophrenia and healthy subjects

Interrogating DNA methylation within schizophrenia risk loci holds promise to identify mechanisms by which genes influence the disease. Based on the hypothesis that allele specific methylation (ASM) of a single CpG, or perhaps CpH, might mediate or mark the effects of genetic variants on disease risk and phenotypes, we explored haplotype specific methylation levels of individual cytosines within a genomic region harbouring the BAG5, APOPT1 and KLC1 genes in peripheral blood of schizophrenia patients and healthy controls. Three DNA fragments located in promoter, intronic and intergenic areas were studied by single-molecule real-time bisulfite sequencing enabling the analysis of long reads of DNA with base-pair resolution and the determination of haplotypes directly from sequencing data. Among 1,012 cytosines studied, we did not find any site where methylation correlated with the disease or cognitive deficits after correction for multiple testing. At the same time, we determined the methylation profile associated with the schizophrenia risk haplotype within the KLC1 fourth intron and confirmed ASM for cytosines located in the vicinity of rs67899457. These genetically associated DNA methylation variations may be related to the pathophysiological mechanism differentiating the risk and non-risk haplotypes and merit further investigation.

Amino acids and acylcarnitines as potential metabolomic markers of schizophrenia: new approaches to diagnostics and therapy

Background. Schizophrenia is a socially significant mental illness with insufficiently studied etiology and pathogenesis. A number of hypotheses of schizophrenia pathogenesis (dopamine, glutamate, kinurenin and serotonin hypotheses) bring together the fact that amino acids are precursors or intermediate metabolic products of these metabolites. Amino acids and their metabolites play an important role as significant substrates and regulators in many metabolic pathways.The aim of this review is to analyze the literature data on the studies of amino acids and acylcarnitines in patients with schizophrenia.Methods. A literature search was conducted using PubMed databases for articles published in English and covering the period from the first articles on this topic, dated 1977 to April 2019. Combinations of the following keywords were used to search for “schizophrenia”, “antipsychotics” and “amino acids”, “acylcarnitines”, “metabolomics”.Results. The review summarizes the data on the content of amino acids and acylcarnitines in the peripheral blood of schizophrenia patients and their dynamics in the course of pharmacotherapy with antipsychotic drugs. The potential of determining amino acids as biomarkers of therapeutic response and side effects, as well as their use in the treatment of patients with schizophrenia, are considered.Conclusion. Further investigation of the spectrum of amino acids and their metabolites with the using of mass spectrometric methods of metabolic analysis can lead to the discovery of new therapeutic targets and strategies, assess their role in the pathophysiology of schizophrenia, identify mechanisms that ensure the development of antipsychotic antipsychotics, and drug-induced side effects antipsychotics, in particular, metabolic syndrome.

Altered expression of the CSMD1 gene in the peripheral blood of schizophrenia patients

BackgroundSchizophrenia (SCZ) is a heritable, refractory, and devastating psychiatric disorder. Previous studies have shown that the variants of CUB and sushi multiple domains 1 (CSMD1) demonstrate significant genome-wide association with SCZ. However, few studies have been conducted on the effect of antipsychotics on the expression levels of CSMD1. This study explored whether a change occurs in the expression of the CSMD1 gene before and after antipsychotic treatment in SCZ patients.MethodsThe study population comprised Han Chinese patients from eastern China, including 32 SCZ patients and 48 healthy controls. The expression of CSMD1 before and after treatment in the SCZ group and between the two groups was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR).ResultsThe expression levels of the CSMD1 gene in the peripheral blood mononuclear cells (PBMCs) of SCZ patients were lower than those in the healthy controls. The expression levels of the CSMD1 gene in the PBMCs of the SCZ patients after antipsychotic treatment were higher than those in the baseline SCZ patients (all P < 0.05).ConclusionsOur results showed that the expression levels of CSMD1 are correlated with the development and treatment of SCZ, providing further evidence for the involvement of CSMD1 in SCZ.

Methylation of the Reelin Gene Promoter in Peripheral Blood and Its Relationship with the Cognitive Function of Schizophrenia Patients

There is a decrease in the expression of the reelin gene (RELN) in the brain of schizophrenia patients, which can underlie observed cognitive abnormalities. It is suggested that this decrease is caused by the hypermethylation of the RELN promoter. The aim of the study was to investigate methylation of the RELN promoter in the peripheral blood of schizophrenia patients and its association with their cognitive deficits. A modified SMRT-BS (single-molecule real-time bisulfite sequencing) was used. We determined the methylation rate of 170 CpG sites within a 1465 bp DNA region containing the entire CpG island in the RELN promoter in 51 schizophrenia patients and 52 healthy controls. All subjects completed a battery of neuropsychological tests. There were no DNA methylation changes associated with schizophrenia. Most CpGs sites were unmethylated in both groups. At the same time, there was a variability in the methylation level of different regions within the promoter. The methylation level in the area from -258 to -151 bp relative to RELN transcription start site was a significant predictor of the index of patients' cognitive functioning if sex, age, smoking, education, and polymorphism rsl858815 had been considered. The positive correlation between the methylation rate in this region and cognitive index suggests that the hypomethylation of the RELN promoter could contribute to the development of cognitive deficits in schizophrenia.

DNA methylation of membrane-bound catechol-O-methyltransferase in Malaysian schizophrenia patients.

This study examined catechol-O-methyltransferase (COMT) DNA methylation in the peripheral blood of schizophrenia patients and also in healthy controls to investigate its potential use as a peripheral biomarker of schizophrenia and its relations with the clinical variables of schizophrenia patients. We examined the DNA methylation levels of COMT using genomic DNA from the peripheral blood of schizophrenia patients (n = 138) and healthy control participants (n = 132); all were Malaysian Malays. The extracted DNA was bisulfite converted, and the percentage methylation ratio value was calculated based on the results following a MethyLight protocol analysis. The percentage methylation ratio of COMT was lower in schizophrenia than it was in the healthy controls (P < 0.001) and was different between the body mass index (P = 0.003) and antipsychotic (P = 0.004) groups. The COMT DNA methylation rate was lower in patients receiving atypical antipsychotics (P = 0.004) and risperidone (P = 0.049) as compared to typical antipsychotics. The Excitement and Depressed subdomains of the Positive and Negative Syndrome Scale were inversely related (P < 0.001) and therefore predictors (Excitement: b = -11.396, t = -4.760, P < 0.001; Depressed: b = -7.789, t = -3.487, P = 0.001) of COMT DNA methylation. Our results suggested that the methylation level was affected by the severity of the clinical symptoms of schizophrenia and might also be influenced by pharmacological treatment. The epigenetic alteration of COMT in the peripheral blood could be a potential peripheral biomarker of schizophrenia.

MicroRNA-137 Inhibits EFNB2 Expression Affected by a Genetic Variant and Is Expressed Aberrantly in Peripheral Blood of Schizophrenia Patients

MicroRNAs (miRNAs) are a class of endogenous and non-coding single-stranded RNAs of approximately 22 nucleotides, many of which are evolutionarily conserved. Genome-wide association studies have identified a robust statistical association between the MIR137 gene and schizophrenia in Europeans, which was replicated in the Han Chinese population in a case-control study. In the previous study, we provided evidence for a significant association between the EFNB2 gene and schizophrenia in Han Chinese subjects. In the current study, we utilized computational analysis, vector construction of point mutations, luciferase reporter assays and gene expression assays including RT-qPCR and western blotting methods to investigate miR-137 directly targeting EFNB2 gene and explore the reversal effect of a genetic variant of SNP rs550067317 in the putative seed-pair region of EFNB2 3′-UTR. We also found that miR-137 could be detected in the peripheral blood of a cohort of first-onset schizophrenia patients and healthy controls, and the area under curve was 0.795 (95% confidence interval 0.700–0.890), which is a middle diagnostic value for disease, suggesting that it might be valuable for diagnosing schizophrenia. In summary, this study would improve our understanding of the role of miR-137 in schizophrenia-associated signaling pathways and identify the genetic basis of rs550067317 for schizophrenia. Furthermore, we provided new evidence for the involvement of miR-137 in the etiology and diagnosis of schizophrenia, which might contribute to the discovery of new biomarkers and therapeutic targets for the disease.

Investigation of Dysregulation of Several MicroRNAs in Peripheral Blood of Schizophrenia Patients.

ObjectiveThe prevalence of schizophrenia is 1%, and it is a debilitating disorder that often results in a shortened lifespan. Peripheral blood samples are good candidates to investigate because they can be easily drawn, and they are widely studied in psychiatric disorders. MicroRNAs are small non-coding RNA transcripts. They regulate the expression of genes by binding to the 3′-untranslated region (UTR) of mRNAs and pointing them to degrade. In this study, we aimed to investigate the expression of miR-9-5p, miR-29a-3p, miR-106-5p, miR-106b-5p, miR-107, miR-125a-3p, and miR-125b-3p in schizophrenia patients and healthy controls.MethodsWe collected blood samples from 16 patients with schizophrenia and 16 healthy controls. MicroRNAs were measured with reverse transcriptase polymerase chain reaction.ResultsSchizophrenia patients showed statistically significant upregulation of five microRNAs: miR9-5p (p=0.002), miR29a-3p (p<0.001), miR106b-5p (p=0.002), miR125a-3p (p<0.001), and miR125b-3p (p=0.018).ConclusionOur results increased the value of the miR106 and miR29 families as potentially and consistently dysregulated in psychiatric disorders. Our results should be considered preliminary, and they need confirmation in future studies with larger sample sizes.

Investigation of fasciculation and elongation protein ζ-1 (FEZ1) in peripheral blood reveals differences in gene expression in patients with schizophrenia.

Schizophrenia (SZ) is a chronic neuropsychiatric disorder characterized by affective, neuromorphological and cognitive impairment, deteriorated social functioning and psychosis with underlying molecular abnormalities, including gene expression changes. Observations have suggested that fasciculation and elongation protein ζ-1 (FEZ1) may be implicated in the pathogenesis of schizophrenia. Nevertheless, our current knowledge of the expression of FEZ1 in peripheral blood of schizophrenia patients remains unclear. The purpose of this study was to identify the characteristic gene expression patterns of FEZ1 in peripheral blood samples from schizophrenia patients. We performed quantitative reverse-transcriptase (qRT-PCR) analysis using peripheral blood from drug-free schizophrenia patients (n = 29) and age and gender-matched general population controls (n = 24). For the identification of FEZ1 gene expression patterns, we applied a comparative threshold cycle (CT) method. A statistically significant difference of FEZ1 mRNA level was revealed in schizophrenia subjects compared to healthy controls (p = 0.0034). To the best of our knowledge, this study is the first describing a down-regulation of FEZ1 gene expression in peripheral blood of patients with schizophrenia. Our results suggested a possible functional role of FEZ1 in the pathogenesis of schizophrenia and confirmed the utility of peripheral blood samples for molecular profiling of psychiatric disorders including schizophrenia. The current study describes FEZ1 gene expression changes in peripheral blood of patients with schizophrenia with significantly down-regulation of FEZ1 mRNA. Thus, our results provide support for a model of SZ pathogenesis that includes the effects of FEZ1 expression.

Alterations of miR-132 are novel diagnostic biomarkers in peripheral blood of schizophrenia patients.

Alterations in microRNAs (miRNAs) have been considered to have diagnostic implications in most diseases, but few studies have reported dysregulated miRNAs in schizophrenia (SCZ). In order to observe an association between miRNAs and SCZ, this study was designed to investigate expression profiling of miRNAs in peripheral blood mononuclear cells (PBMCs). miRNA microarray technology was employed to compare the expression of miRNAs in PBMCs from SCZ patients (n=105) and normal controls (n=130), and real-time quantitative polymerase chain reaction (QPCR) was used to analyze the results. Several important miRNA levels were examined before and after antipsychotic treatment in first-onset SCZ patients. In addition, an SCZ-like rat model was established using dizocilpine (MK-801), and miR-132 expression in PBMCs and whole-brain tissue from SCZ-like rats was studied using QPCR. In humans, dysregulated miRNAs were observed before treatment and QPCR verified that miR-132, miR-134, miR-1271, miR-664(⁎), miR-200c and miR-432 levels were significantly decreased (P<0.01 for all) in PBMCs of SCZ patients compared with healthy controls. After antipsychotic treatment there was a marked increase in miR-132 (P<0.01), miR-664(⁎) (P<0.05) and miR-1271 (P<0.05) levels in SCZ patients compared with the levels before treatment. In the animal assays, miR-132 levels declined in PBMCs and whole-brain tissues (both P<0.05) of the SCZ-like rats compared to controls. For the first time, our results suggest that miR-132 is a potential and superior biomarker in peripheral blood that will allow discrimination of SCZ patients from healthy controls.

MicroRNA-382 expression is elevated in the olfactory neuroepithelium of schizophrenia patients

Schizophrenia is a common neuropsychiatric disorder that has a strong genetic component. MicroRNAs (miRNAs) have been implicated in neurodevelopmental and psychiatric disorders including schizophrenia, as indicated by their dysregulation in post-mortem brain tissues and in peripheral blood of schizophrenia patients. The olfactory epithelium (OE) is one of the few accessible neural tissues that contain neurons and their stem cells. Previous studies showed that OE-derived tissues and cells can be safely and easily collected from live human subjects and may provide a “window” into neuronal processes involved in disorders such as schizophrenia, while avoiding the limitations of using postmortem brain samples or non-neuronal tissues. In this study, we found that the brain-enriched miR-382 (miR-382-5p) expression was elevated in in vitro cultured olfactory cells, in a cohort of seven schizophrenia patients compared with seven non-schizophrenic controls. MiR-382 elevation was further confirmed in laser-capture microdissected OE neuronal tissue (LCM-OE), enriched for mature olfactory neurons, in a cohort of 18 schizophrenia patients and 18 non-schizophrenic controls. In sharp contrast, miR-382 expression could not be detected in lymphoblastoid cell lines generated from schizophrenic or non-schizophrenic individuals. We further found that miR-382 directly regulates the expression of two genes, FGFR1 and SPRY4, which are downregulated in both the cultured olfactory cells and LCM-OE derived from schizophrenia patients. These genes are involved in the fibroblast growth factor (FGF) signaling pathway, while impairment of this pathway may underlie abnormal brain development and function associated with schizophrenia. Our data suggest that miR-382 elevation detected in patients' OE-derived samples might serve to strengthen current biomarker studies in schizophrenia. This study also illustrates the potential utility of OE-derived tissues and cells as surrogate samples for the brain.