Pathogenesis Of Schizophrenia Research Articles

Psychiatric manifestations of anti-N-methyl-D-aspartate receptor encephalitis: A case report.

Psychiatric manifestations of anti-N-methyl-D-aspartate receptor encephalitis: A case report.

Astrocytes in schizophrenia.

Schizophrenia is a severe and clinically heterogenous mental disorder affecting approximately 1% of the population worldwide. Despite tremendous achievements in the field of schizophrenia research, its precise aetiology remains elusive. Besides dysfunctional neuronal signalling, the pathophysiology of schizophrenia appears to involve molecular and functional abnormalities in glial cells, including astrocytes. This article provides a concise overview of the current evidence supporting altered astrocyte activity in schizophrenia, which ranges from findings obtained from post-mortem immunohistochemical analyses, genetic association studies and transcriptomic investigations, as well as from experimental investigations of astrocyte functions in animal models. Integrating the existing data from these research areas strongly suggests that astrocytes have the capacity to critically affect key neurodevelopmental and homeostatic processes pertaining to schizophrenia pathogenesis, including glutamatergic signalling, synaptogenesis, synaptic pruning and myelination. The further elucidation of astrocytes functions in health and disease may, therefore, offer new insights into how these glial cells contribute to abnormal brain development and functioning underlying this debilitating mental disorder.

Understanding the role of gut microbiota in the pathogenesis of schizophrenia.

Schizophrenia is a chronic mental disorder with marked symptoms of hallucination, delusion, and impaired cognitive behaviors. Although multidimensional factors have been associated with the development of schizophrenia, the principal cause of the disorder remains debatable. Microbiome involvement in the etiology of schizophrenia has been widely researched due to the advancement in sequencing technologies. This review describes the contribution of the gut microbiome in the development of schizophrenia that is facilitated by the gut-brain axis. The gut microbiota is connected to the gut-brain axis via several pathways and mechanisms, that are discussed in this review. The role of the oral microbiota, probiotics and prebiotics in shaping the gut microbiota are also highlighted. Lastly, future perspectives for microbiome research in schizophrenia are addressed.

Late schizophrenia

Introduction. The problem of late schizophrenia is one of the most controversial in clinicalpsychiatry. The organic factors that accompany the aging process make diagnosis difficult. Based on the consensus statement from an international group of experts in the field, this review discusses the features of schizophrenia in old age with a debut at a young age, late-onset schizophrenia (illness onset after 40 years of age) and very-late-onset schizophrenia-like psychosis (onset after 60 years). Method. The author conducted a study of MEDLINE sources on late schizophrenia.Results.This review provides data on the prevalence, neuroanatomy, pathogenesis, clinical presentation and treatment of schizophrenia in the elderly.Conclusion. Late schizophrenia is becoming a serious public health problem worldwide. Particularly relevant are the problems of the course of the disease, medical care and comorbidity in older psychiatric patients (general and illness-related), and treatment concerns related to the use of antipsychotics

Сellular and Molecular Mechanisms of Proinflammatory Monocytes Participation in the Pathogenesis of Mental Disorders. Part 2

Introduction: at the end of the last century, the macrophage-T-lymphocyte theory of the development of mental disorders was formulated. It underlines the important role of monocytes/macrophages and cytokines produced by them in the pathogenesis of schizophrenia, bipolar affective disorder (BAD) and depression. The first part of our review is dedicated to the analysis of the mechanisms of cellular and molecular interactions of activated monocytes/macrophages synthesizing proinflammatory CD16 receptors with endothelial cells, platelets, and microglia cells in the pathogenesis of systemic immune inflammation, including CNS as a result of violation of the integrity of the blood-brain barrier (BBB), activate microglia and cause the development of neuroinflammation in patients.The aim of work: to analyze and summarize the results of the main scientific publications for the role of cell-molecular mechanisms of the monocyte-macrophage immunity link activation in the pathogenesis of schizophrenia, BAD and depression. Material and methods: keywords “proinflammatory monocytes, cytokines, chemokines, molecules of cell adhesion, microglia, neuroinflammation, mental disorders” were used to search for data published over the past 20 years in domestic and foreign studies in PubMed, eLIBRARY, Science direct and EMBASE.Conclusion: the present review is dedicated to the analysis of the latest research data concerning an increase in the number of active circulating monocytes/macrophages and an increased level of proinflammatory cytokines, chemokines and receptors for them produced by monocytes in patients with schizophrenia, BAD and depression, what allows to associate these disorders with systemic immune inflammation. The data reasearches on cellular and molecular mechanisms of proinflammatory monocytes/macrophages interaction with microglia cells that initiate neuroinflammation in the CNS and lead to destabilization of brain function and the development of psychotic disorders are presented. The association of high levels of proinflammatory cytokines with somatic comorbidity, including metabolic syndrome, diabetes, atherosclerosis and other systemic diseases is shown in patients with mental disorders.Findings: the presented review of the research data allows us to better understand the cellular and molecular aspects of activation of the monocyte-macrophage immunity link in the development of neuroinflammation and cognitive decline in the pathogenesis of mental disorders, as well as helps in the search for informative biomarkers of the positive treatment of these disorders and the new approaches in the treatment of patients, based on the complex use of psychotropic and anti-inflammatory drugs.

Platelet Enzymes of Glutathione Metabolism in Patients with Late-Onset Schizophrenic Spectrum Disorders

Background: basing on the hypothesis that oxidative stress participates in schizophrenia pathogenesis, the authors suggested that the activities of glutathione reductase (GR) and glutathione-S-transferase (GST), the enzymes metabolizing the central antioxidant glutathione, are altered in patients with schizophrenia spectrum disorders.Objective: determination of activity of platelet glutathione reductase (GR) and glutathione-S-transferase (GST) in patients with late-onset schizophrenic spectrum disorders (LOS - spectrum psychoses) and evaluation of their possible connection to clinical indicators.Patients and methods: 28 female in-patients aged 45–86 years with LOS-spectrum psychoses were examined: schizophrenia (n = 16), schizoaffective disorder (n = 6), chronic delusional disorder (n = 6). A control group of women of the same age range without mental and neurological diseases was recruited. Platelet GR and GST activities in patients were determined before and after the course of pharmacotherapy, and in the control group - only once.Results: assessment of the patients’ symptoms’ severity using PANSS, HAMD, and MMSE was carried out before and after the course of pharmacotherapy (at the 28th day of the therapy course). The efficacy of therapy was determined by the change in the PANSS and HAMD total score. While the GR activity did not differ significantly in patients and in the control group, GST activity was found substantially and significantly reduced in patients (before and after the course of therapy) compared with the control group, although GST activity in patients did not significantly change during their treatment. In both cases (GR and GST), three patients were observed among the patients with enzymatic activity exceeding > 1.5 times the medians in the group. After the course of treatment, the activity of enzymes decreased to a level within the range of control values or values for other patients.Conclusion: the results of a pilot study indicate the promise of determining the activity of GR and GST in a group of patients with LOS-spectrum endogenous psychoses to distinguish among them subgroups with glutathione metabolism abnormalities that correlate with clinical and pathopsychological features.

The frontal pole and cognitive insight in schizophrenia

Absence of insight owing to impaired self-reflection and lack of touch with reality is a hallmark of schizophrenia. Functional imaging studies in healthy individuals have implicated the frontal pole (FP), sub-division of the prefrontal cortex in self-reflective processes. Despite the significance of self-referential processing in the pathogenesis of schizophrenia, the relationship between FP volume and cognitive insight in this disorder is underexplored. We examined the relationship between cognitive insight and volume of FP using precise manual morphometry of high resolution magnetic resonance images in 19 schizophrenia patients (SCZ) and 21 healthy-volunteers (HV). The manual morphometry technique was replicated from a previous study based on a cytoarchitectonically and functionally valid definition of FP and cognitive insight was measured using Beck's cognitive insight scale. Left frontal pole volume was a significant predictor of self-reflection sub-score of Beck's cognitive insight scale (β=0.68; t = 2.86; p = 0.01). A significant inverse relationship between age and bilateral FP volumes was noted in HV (left FP - r=-0.45; p = 0.04; right FP - r=-0.57; p = 0.008) but not in SCZ (p>0.05). Our findings provide anatomical substrates to devise intervention strategies targeting cognitive insight, thereby improving treatment adherence and functional outcomes.

Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia.

Recent studies suggest a primary role of oxidative stress in an early phase of the pathogenesis of schizophrenia and a strong neurobiological link has been found between dopaminergic system dysfunction, microglia overactivation, and oxidative stress. Different risk factors for schizophrenia increase oxidative stress phenomena raising the risk of developing psychosis. Oxidative stress induced by first-generation antipsychotics such as haloperidol significantly contributes to the development of extrapyramidal side effects. Haloperidol also exerts neurotoxic effects by decreasing antioxidant enzyme levels then worsening pro-oxidant events. Opposite to haloperidol, second-generation antipsychotics (or atypical antipsychotics) such as risperidone, clozapine, and olanzapine exert a strong antioxidant activity in experimental models of schizophrenia by rescuing the antioxidant system, with an increase in superoxide dismutase and glutathione (GSH) serum levels. Second-generation antipsychotics also improve the antioxidant status and reduce lipid peroxidation in schizophrenic patients. Interestingly, second-generation antipsychotics, such as risperidone, paliperidone, and in particular clozapine, reduce oxidative stress induced by microglia overactivation, decreasing the production of microglia-derived free radicals, finally protecting neurons against microglia-induced oxidative stress. Further, long-term clinical studies are needed to better understand the link between oxidative stress and the clinical response to antipsychotic drugs and the therapeutic potential of antioxidants to increase the response to antipsychotics.

Incongruent Expression of Brain-Derived Neurotrophic Factor and Cortisol in Schizophrenia: Results from a Randomized Controlled Trial of Laughter Intervention.

ObjectiveSchizophrenia has been associated with dysfunction of the hypothalamic-pituitary-adrenal axis. Furthermore, alterations in neurotrophic factors might contribute to the pathogenesis of schizophrenia. We aimed to evaluate the effects of a simulated laughter intervention on the levels of cortisol and BDNF and to determine whether the effects associated with simulated laughter could be sustained after discontinuation of the intervention.MethodsIn this randomized controlled study, patients with schizophrenia according to DSM-IV clinical criteria were randomly assigned to receive either 8-week-long simulated laughter intervention (n=32) or treatment-as-usual group (control group, n=27). The serum levels of BDNF and cortisol were measured at baseline, week 8, and four weeks after discontinuation (week 12) of the intervention program. ResultsAfter an 8-week simulated laughter intervention, the laughter group had significantly higher levels of BDNF; however, four weeks after discontinuation of the intervention, the levels of BDNF significantly dropped. Interestingly, the levels of cortisol did not change significantly at week 8, but they were significantly elevated at week 12. The levels of BDNF and cortisol in the control group did not change significantly between week 0 and week 8. ConclusionThese findings suggest that the simulated laughter intervention has an early effect on neurogenesis with a significant delayed effect on stress regulation in subjects with schizophrenia.

Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population.

Schizophrenia is a severe neuropsychiatric disorder with core features including hallucinations, delusions, and cognition deficits. Accumulating evidence has implicated abnormal DNA methylation in the development of schizophrenia. However, the mechanisms by which DNA methylation changes alter the risk for schizophrenia remain largely unknown. We recently carried out a DNA methylome study of peripheral blood samples from 469 first-episode patients with schizophrenia and 476 age- and gender-matched healthy controls of Han Chinese origin. Genomic DNA methylation patterns were quantified using an Illumina Infinium Human MethylationEPIC BeadChip. We identified multiple differentially methylated positions (DMPs) and regions between patients and controls. The most significant DMPs were annotated to genes C17orf53, THAP1 and KCNQ4 (KV7.4), with Bonferroni-adjusted P values of [Formula: see text], [Formula: see text], and [Formula: see text], respectively. In particular, KCNQ4 encodes a voltage-gated potassium channel of the KV7 family, which is linked to neuronal excitability. The genes associated with top-ranked DMPs also included many genes involved in nervous system development, such as LIMK2 and TMOD2. Gene ontology analysis of the differentially methylated genes further identified strong enrichment of neuronal networks, including neuron projection extension, axonogenesis and neuron apoptotic process. Finally, we provided evidence that schizophrenia-associated epigenetic alterations co-localize with genetic susceptibility loci. By focusing on first-episode schizophrenia patients, our investigation lends particularly strong support for an important role of DNA methylation in schizophrenia pathogenesis unconfounded by the effects of long-term antipsychotic medication or disease progression. The observed DNA methylation aberrations in schizophrenia patients could potentially provide a valuable resource for identifying diagnostic biomarkers and developing novel therapeutic targets to benefit schizophrenia patients.

MicroRNA-195 predicts olanzapine response in drug-free patients with schizophrenia: A prospective cohort study.

Disturbances of microRNA-195 have been implicated in the pathogenesis of schizophrenia. However, microRNA-195 levels in schizophrenia are controversial. To the best of our knowledge, this is the first study to examine microRNA-195 levels in untreated schizophrenia patients and their relationship to olanzapine response. We recruited 81 untreated schizophrenia patients and 96 healthy controls. The patients received 2 months olanzapine treatment. MicroRNA-195 levels in peripheral blood mononuclear cells were measured using quantitative real-time polymerase chain reaction testing. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale. No significant differences in microRNA-195 levels were found between patients and healthy controls (p > 0.05). Olanzapine significantly reduced microRNA-195 levels after 2 months treatment (p = 0.003). Interestingly, microRNA-195 levels decreased significantly in responders (p = 0.010), but not in non-responders (p > 0.05). Both baseline microRNA-195 levels (p = 0.027, p = 0.030) and the reduction rate of microRNA-195 levels (p = 0.034, p = 0.044) were positively associated with the reduction rate of Positive and Negative Syndrome Scale total score and general psychopathological subscale score. Multiple stepwise regression analysis revealed that baseline microRNA-195 level was an independent contributor to the reduction in Positive and Negative Syndrome Scale total score and the general psychopathological subscale score (p = 0.018, p = 0.030). Finally, logistic regression analysis suggested that baseline microRNA-195 level can serve as a biomarker for response to olanzapine (p = 0.037). Our data indicate that microRNA-195 level may predict symptomatic improvement and olanzapine response in schizophrenia patients, suggesting that microRNA-195 should be considered as a potential therapeutic target for antipsychotics.

CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia

GABAergic dysfunctions have been implicated in the pathogenesis of schizophrenia, especially the associated cognitive impairments. The GABA synthetic enzyme glutamate decarboxylase 67-kDa isoform (GAD67) encoded by the GAD1 gene is downregulated in the brains of patients with schizophrenia. Furthermore, a patient with schizophrenia harboring a homozygous mutation of GAD1 has recently been discovered. However, it remains unclear whether loss of function of GAD1 leads to the symptoms observed in schizophrenia, including cognitive impairment. One of the obstacles faced in experimental studies to address this issue is the perinatal lethality of Gad1 knockout (KO) mice, which precluded characterization at the adult stage. In the present study, we successfully generated Gad1 KO rats using CRISPR/Cas9 genome editing technology. Surprisingly, 33% of Gad1 KO rats survived to adulthood and could be subjected to further characterization. The GABA concentration in the Gad1 KO cerebrum was reduced to ~52% of the level in wild-type rats. Gad1 KO rats exhibited impairments in both spatial reference and working memory without affecting adult neurogenesis in the hippocampus. In addition, Gad1 KO rats showed a wide range of behavioral alterations, such as enhanced sensitivity to an NMDA receptor antagonist, hypoactivity in a novel environment, and decreased preference for social novelty. Taken together, the results suggest that Gad1 KO rats could provide a novel model covering not only cognitive deficits but also other aspects of the disorder. Furthermore, the present study teaches an important lesson: differences between species should be considered when developing animal models of human diseases.

Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia.

BackgroundThe pathophysiology of schizophrenia, a major psychiatric disorder, remains elusive. In this study, the role of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) families, belonging to the ligand-activated nuclear receptor superfamily, in schizophrenia, was analyzed.MethodsThe PPAR/RXR family genes were screened by exploiting molecular inversion probe (MIP)-based targeted next-generation sequencing (NGS) using the samples of 1,200 Japanese patients with schizophrenia. The results were compared with the whole-genome sequencing databases of the Japanese cohort (ToMMo) and the gnomAD. To reveal the relationship between PPAR/RXR dysfunction and schizophrenia, Ppara KO mice and fenofibrate (a clinically used PPARα agonist)-administered mice were assessed by performing behavioral, histological, and RNA-seq analyses.FindingsOur findings indicate that c.209–2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene are risk variants for schizophrenia. The c.209–2delA variant generated a premature termination codon. The three missense variants significantly decreased the activity of PPARα as a transcription factor in vitro. The Ppara KO mice exhibited schizophrenia-relevant phenotypes, including behavioral deficits and impaired synaptogenesis in the cerebral cortex. Oral administration of fenofibrate alleviated spine pathology induced by phencyclidine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Furthermore, pre-treatment with fenofibrate suppressed the sensitivity of mice to another NMDA receptor antagonist, MK-801. RNA-seq analysis revealed that PPARα regulates the expression of synaptogenesis signaling pathway-related genes.InterpretationThe findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPARα-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPARα can serve as a novel therapeutic target for schizophrenia.

G Protein-Coupled Estrogen Receptor 1 Knockout Deteriorates MK-801-Induced Learning and Memory Impairment in Mice.

The role of estrogen receptors in neuroprotection and cognition has been extensively studied in humans over the past 20 years. Recently, studies have shifted their focus to the use of selective estrogen receptor modulators in the treatment of mental illnesses in the central nervous system. We conducted this study to test the behavioral changes shown by G protein-coupled estrogen receptor 1 knockout (GPER1 KO) and wild-type (WT) mice with MK-801-induced schizophrenia (SZ). GPER1 KO and WT mice received intraperitoneal injections of MK-801 for 14 continuous days. Behavioral, learning and memory, and social interaction changes were evaluated by using the IntelliCage system, open-field, three-chamber social interaction, and novel object recognition tests (NORT). The protein expression levels of the NR2B/CaMKII/CREB signaling pathway were tested via Western blot analysis. The KO SZ group was more likely to show impaired long-term learning and memory function than the WT SZ group. Learning and memory functions were also impaired in the KO Con group. MK-801 administration to the GPER1-KO and WT groups resulted in memory deficiencies and declining learning capabilities. GPER1 deficiency downregulated the expression levels of proteins related to the NR2B/CaMKII/CREB signaling pathway. Our study suggested that GPER1 played an important role in cognitive, learning, and memory functions in the MK-801-induced mouse model of SZ. The mechanism of this role might partially involve the downregulation of the proteins related to the NR2B/CaMKII/CREB signaling pathway. Further studies should focus on the effect of GPER1 on the pathogenesis of SZ in vivo and in vitro.

Support vector machine-based classification of schizophrenia patients and healthy controls using structural magnetic resonance imaging from two independent sites.

Structural brain alterations have been repeatedly reported in schizophrenia; however, the pathophysiology of its alterations remains unclear. Multivariate pattern recognition analysis such as support vector machines can classify patients and healthy controls by detecting subtle and spatially distributed patterns of structural alterations. We aimed to use a support vector machine to distinguish patients with schizophrenia from control participants on the basis of structural magnetic resonance imaging data and delineate the patterns of structural alterations that significantly contributed to the classification performance. We used independent datasets from different sites with different magnetic resonance imaging scanners, protocols and clinical characteristics of the patient group to achieve a more accurate estimate of the classification performance of support vector machines. We developed a support vector machine classifier using the dataset from one site (101 participants) and evaluated the performance of the trained support vector machine using a dataset from the other site (97 participants) and vice versa. We assessed the performance of the trained support vector machines in each support vector machine classifier. Both support vector machine classifiers attained a classification accuracy of >70% with two independent datasets indicating a consistently high performance of support vector machines even when used to classify data from different sites, scanners and different acquisition protocols. The regions contributing to the classification accuracy included the bilateral medial frontal cortex, superior temporal cortex, insula, occipital cortex, cerebellum, and thalamus, which have been reported to be related to the pathogenesis of schizophrenia. These results indicated that the support vector machine could detect subtle structural brain alterations and might aid our understanding of the pathophysiology of these changes in schizophrenia, which could be one of the diagnostic findings of schizophrenia.

Association of APOE E2 and low-density lipoprotein with depressive symptoms in Chinese senile schizophrenia inpatients: A cross-sectional study

BackgroundSchizophrenia is considered to occur due to both environmental and genetic factors. Depressive symptoms and apolipoprotein E (APOE) gene polymorphisms are involved in the pathogenesis of schizophrenia. However, the effect of APOE gene polymorphism on depressive symptoms has never been investigated among Chinese elderly schizophrenia patients. ObjectiveThis cross-sectional study aimed to determine the effect of APOE gene polymorphism on blood lipid metabolism and depressive symptoms among elderly schizophrenia patients. MethodA total of 301 elderly schizophrenia patients (161 males, age ranges from 60 to 92 years, with an average age of 67.31 ± 6.667) were included in the study. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). APOE gene polymorphisms were determined by polymerase chain reaction (PCR). Correlations between GDS and serum low-density lipoprotein (LDL) levels with APOE genotypes were assessed. ResultsThe concentration of LDL in the APOE E2 group was significantly lower than those in the APOE E3 and APOE E4 groups, and the GDS scores in the APOE E2 and APOE E3 groups were higher than those in the APOE E4 group. Using partial correlation analysis and controlling the duration of disease and hyperlipidemia, we found that GDS scores were significantly correlated with LDL (r = −0.179, p = 0.025). ConclusionsThe APOE E2 genotype is associated with more depressive symptoms and lower serum LDL in elderly Chinese schizophrenia patients, and there is a negative correlation between depressive symptoms and LDL.

Alteration in the expression of inflammatory cytokines in primary hippocampal astrocytes in response to MK-801 through ERK1/2 and PI3K signals

Our previous study showed that dizocilpine (MK-801) induced schizophrenia-like behavior in rats, enhanced GFAP expression, and activated primary cultured hippocampal astrocytes. Astrocytes play an essential role in neuroinflammation and contribute to the crosstalk that generates chronic neuro-inflammation in neurological diseases. However, the effects of MK-801 treatment on astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. To address this issue, IL1β, IL6, TNFα and IL10 expression and secretion levels were evaluated in hippocampal astrocytes in response to MK-801 for 24 h by ELISA and real-time PCR, with and without pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. Cell apoptosis, viability, and proliferation were also examined. MK-801 treatment did not induce hippocampal astrocytes apoptosis or proliferation, however, MK-801 enhanced astrocytes viability. Additionally, the expression and secretion levels of IL1β, IL6 and TNFα were elevated, but that of IL10 was decreased, in which ERK1/2 and PI3K signals were involved. These findings suggest that hippocampal astrocytes may regulate the expressions of inflammatory cytokines through ERK1/2 and PI3K signaling pathway to participate in the pathogenesis of schizophrenia.

Widespread transcriptional disruption of the microRNA biogenesis machinery in brain and peripheral tissues of individuals with schizophrenia

In schizophrenia, altered transcription in brain and peripheral tissues may be due to altered expression of the microRNA biogenesis machinery genes. In this study, we explore the expression of these genes both at the cerebral and peripheral levels. We used shinyGEO application to analyze gene expression from ten Gene Expression Omnibus datasets, in order to perform differential expression analyses for eight genes encoding the microRNA biogenesis machinery. First, we compared expression of the candidate genes between control subjects and individuals with schizophrenia in postmortem cerebral samples from seven different brain regions. Then, we compared the expression of the candidate genes between control subjects and individuals with schizophrenia in three peripheral tissues. In brain and peripheral tissues of individuals with schizophrenia, we report distinct altered expression patterns of the microRNA biogenesis machinery genes. In the dorsolateral prefrontal cortex, associative striatum and cerebellum of individuals with schizophrenia, we observed an overexpression pattern of some candidate genes suggesting a heightened miRNA production in these brain regions. Additionally, mixed transcriptional abnormalities were identified in the hippocampus. Moreover, in the blood and olfactory epithelium of individuals with schizophrenia, we observed distinct aberrant transcription patterns of the candidate genes. Remarkably, in individuals with schizophrenia, we report DICER1 overexpression in the dorsolateral prefrontal cortex, hippocampus and cerebellum as well as a congruent DICER1 upregulation in the blood compartment suggesting that it may represent a peripheral marker. Transcriptional disruption of the miRNA biogenesis machinery may contribute to schizophrenia pathogenesis both in brain and peripheral tissues.

Elevated Platelet Parameter in First-Episode Schizophrenia Patients: A Cross-Sectional Study

Serotonin (5-HT) and inflammation are 2 major hypotheses in schizophrenia (SZ) pathogenesis, both of which involve platelets. However, the association between platelet and SZ has not been well studied. The aim of this study was to evaluate changes of platelet count (PLT), mean platelet volume (MPV), platelet-large cell ratio (P-LCR), platelet distribution width (PDW), and plateletcrit (PCT) in patients with first-episode schizophrenia (FES). Meanwhile, 3 inflammation markers, including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR), were evaluated. Complete blood count of 106 FES patients, 82 first-episode depression (FED) patients, and 120 healthy controls (HCs) were compared. In addition, PLR, NLR, and MLR were calculated and compared among 3 groups. Our data suggested that PLT, MPV, P-LCR, PDW, PCT, NLR, PLR, and MLR in FES patients were significantly increased than those in the HCs (P < 0.01 or P < 0.05, respectively). PLT, PCT, PLR, and MLR in FED patients were significantly higher than those in the HCs (P < 0.01). However, no significant difference in MPV, P-LCR, and NLR was identified between FED patients and HCs (P > 0.05). Moreover, MPV, P-LCR, PDW, NLR, and MLR in FES patients were significantly higher than those in FED patients (P < 0.01 or P < 0.05, respectively). The elevation of PLT, MPV, P-LCR, PDW, PCT, NLR, PLR, and MLR in FES patients supported 5-HT and inflammation hypotheses in SZ pathogenesis. Further, our data suggested that increasing levels of MPV, P-LCR, PDW, NLR, and MLR might help to distinguish FES from FED. Clinical Trials.gov ID: 2018JJ2580.

Microbiome Profiling Reveals Gut Dysbiosis in the Metabotropic Glutamate Receptor 5 Knockout Mouse Model of Schizophrenia.

Schizophrenia (SZ) is a psychiatric disorder that constitutes one of the top 10 global causes of disability. More recently, a potential pathogenic role for the gut microbial community (microbiota) has been highlighted, with numerous studies describing dysregulated microbial profiles in SZ patients when compared to healthy controls. However, no animal model of SZ has previously recapitulated the gut dysbiosis observed clinically. Since the metabotropic glutamate receptor 5 (mGlu5) knockout mice provide a preclinical model of SZ with strong face and predictive validity, in the present study we performed gut microbiome profiling of mGlu5 knockout (KO) and wild-type (WT) mice by 16S rRNA sequencing of bacterial genomic DNA from fecal samples, analyzing bacterial diversity and taxonomic composition, as well as gastrointestinal parameters as indicators of gut function. We found a significant genotype difference in microbial beta diversity. Analysis of composition of microbiomes (ANCOM) models were performed to evaluate microbiota compositions, which identified a decreased relative abundance of the Erysipelotrichaceae family and Allobaculum genus in this mouse model of SZ. We also identified a signature of bacteria discriminating between the genotypes (KO and WT), consisting of the Erysipelotrichales, Bacteroidales, and Clostridiales orders and macroscopic gut differences. We thus uncovered global differential community composition in the gut microbiota profile between mGlu5 KO and WT mice, outlining the first evidence for gut dysbiosis in a genetic animal model of SZ. Our findings suggest that this widely used preclinical model of SZ also has substantial utility for investigations of gut dysbiosis and associated signaling via the microbiota–gut–brain axis, as potential modulators of SZ pathogenesis. Our discovery opens up new avenues to explore gut dysbiosis and its proposed links to brain dysfunction in SZ, as well as novel therapeutic approaches to this devastating disorder.