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Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor - particularly the ratio of GluN2A and GluN2B subunits - in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37). We sought to test whether changes in these measures are specific to the subset of schizophrenia cases with high levels of inflammation-related mRNAs, defined as a high inflammatory subgroup. Quantitative autoradiography was used to detect 'functional' NMDARs ([3H]MK-801), GluN1-coupled-GluN2A subunits ([3H]CGP-39653), and GluN1-coupled-GluN2B subunits ([3H]Ifenprodil). Quantitative RT-PCR was used to measure NMDAR subunit transcripts (GRIN1, GRIN2A and GRIN2B). The ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were calculated as an index of putative NMDAR composition. We found: 1) GluN2A binding, and 2) the ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were lower in schizophrenia cases versus controls (p < 0.05), and 3) lower GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNA ratios were exaggerated in the high inflammation/schizophrenia subgroup compared to the low inflammation/control subgroup (p < 0.05). No other NMDAR-related indices were significantly changed in the high inflammation/schizophrenia subgroup. This suggests that neuroinflammation may alter NMDAR stoichiometry rather than targeting total NMDAR levels overall, and future studies could aim to determine if anti-inflammatory treatment can alleviate this aspect of NMDAR-related pathology. [ABSTRACT FROM AUTHOR]

Abstract: Metabotropic glutamate receptors 2 and 3 (mGluR2/3) have been shown as efficient targets for antipsychotic intervention. We therefore investigated the receptor density of mGluR2/3 in the dorsolateral prefrontal cortex (dlPFC; Brodman area 46) of schizophrenia/schizoaffective patients (n=37) and matched controls (n=37) using receptor autoradiography. No difference in mGluR2/3 density was identified in relation to schizophrenia diagnosis. Overall and in individual groups, a negative correlation of mGluR2/3 density and age at death has been found. These and previous results suggest that density of mGluR2/3 in the dlPFC is less likely to impact on the efficiency of the mGluR2/3 agonist in treating schizophrenia symptoms. [Copyright &y& Elsevier]

Objective: This study was to examine the alterations in metabolic parameters, anti-oxidant superoxide dismutase (SOD), inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and microbiota after 24-week risperidone treatment in drug naïve, normal weight, first episode schizophrenia patients; the study further examined the relationship between metabolic changes and changes in microbiota.Methods: Forty-one patients completed the 24-week study and 41 controls were enrolled in this study. Metabolic parameters, SOD, hs-CRP and the copy numbers of 5 fecal bacteria were measured at baseline (both groups) and at different time points (patients only).Results: Patients had significantly lower numbers of fecal Bifidobacterium spp., Escherichia coli, Lactobacillus spp. compared with healthy controls (HC) (ps < 0.001); in contrast, the numbers of fecal Clostridium coccoides group were significantly higher in the patient group compared with HC (p < 0.001). After 24-week risperidone treatment, there were significant increases in body weight, BMI, fasting blood-glucose, triglycerides, LDL, hs-CRP, SOD and HOMA-IR (p < 0.001), significant increases in the numbers of fecal Bifidobacterium spp. and E. coli (ps < 0.001), and significant decreases in the numbers of fecal Clostridium coccoides group and Lactobacillus spp. (ps < 0.001). Hierarchical multiple linear regression analysis shows that after controlling for potential confounding variables, only the changes in fecal Bifidobacterium spp., among 4 types of fecal bacteria, entered into the model and significantly correlated with the changes in weight (unstandardized coefficient B = 4.413, R2 change = 0.167, p = 0.009) and BMI (B = 1.639, R2 change = 0.172, p = 0.008) after 24-week treatment.Conclusion: Drug naïve, first episode schizophrenia patients show abnormalities in microbiota composition. Risperidone treatment causes significant changes in certain fecal bacteria, which are likely associated with antipsychotic medication induced metabolic changes. [ABSTRACT FROM AUTHOR]

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5'-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5'-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 5 (mGluR5) is involved in hippocampal-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippocampal mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem samples from the hippocampal CA1 region of schizophrenia subjects and matched controls (n = 20/group). Protein levels of mGluR5 (total: 42%, p < 0.001; monomer: 25%, p = 0.011; dimer: 52%, p < 0.001) and mGluR5 trafficking molecules (Norbin: 47%, p < 0.001; Tamalin: 34%, p = 0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippocampus of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippocampus of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder. [ABSTRACT FROM AUTHOR]

Immune deregulation has been postulated to be one of the mechanisms underlying the pathogenesis of tardive dyskinesia (TD). We hypothesized that interleukins would have a link with TD in schizophrenia patients. In this study, the serum IL-2, IL-6 and IL-8 levels were examined by enzyme-linked immunosorbent assay (ELISA) in schizophrenia patients with TD (n = 48) and without TD (n = 45), and healthy controls (n = 44). The psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). The severity of TD was evaluated using Abnormal Involuntary Movement Scale (AIMS). The results showed that serum IL-2, IL-6 and IL-8 levels were significantly different among schizophrenia patients with TD and without TD and normal controls. Moreover, IL-2 level was significantly correlated with PANSS positive subscale and general subscale in patients with TD and without TD. In addition, IL-2 level was positively correlated with AIMS score in TD patients. The results supported that immune disturbance is related to the schizophrenia patients, especially to the patients with TD and ILs might play an important role in the pathophysiology of schizophrenia patients with TD. [ABSTRACT FROM AUTHOR]

Many genes associated with dopamine (DA) and norepinephrine (NE) systems influence cognitive deficits of schizophrenia patients, but one key enzyme is dopamine beta-hydroxylase (DBH), which converts DA to NE and whose activity and levels are under strong genetic control. This study examines the association of the 19 bp insertion/deletion (Ins/Del) polymorphism in the 5' flank of the DBH gene with cognitive deficits in first-episode schizophrenic patients (FEP). We assessed the cognitive function in 195 FEP and 304 healthy controls using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The 19 bp Ins/Del polymorphism of DBH gene was genotyped. Our results showed that the allelic and genotypic frequencies of the 19 bp Ins/Del polymorphism significantly differed between FEP and healthy controls (both p < 0.05). Cognitive test scores were significantly lower in FEP than healthy controls on all scales (all p < 0.001) except for the visuospatial/constructional index (p > 0.05). Immediate memory abilities significantly differed by genotype (p<0.05) but not genotype×diagnosis. Immediate memory score was lower in FEP with DBH5'-Del/Del genotype (61.3 ± 17.2) than those with DBH5'-Ins/Ins genotype (68.6 ± 16.2; p < 0.05). The 19 bp Del allele was associated with poorer immediate memory performance than the Ins allele in FEP (p < 0.05). However, healthy controls did not show any differences in cognitive function indices between the Ins and Del for either the allele or genotype of the 19 bp Ins/Del polymorphism. Our findings suggest that the DBH5'-Ins/Del polymorphism may play a role in susceptibility to FEP. The DBH5'-Ins/Del polymorphism may also influence immediate memory in FEP. Moreover, FEP had poorer cognitive function than healthy controls in all examined cognitive domains except for the visuospatial/constructional index. [ABSTRACT FROM AUTHOR]

Abstract: Many genes associated with dopamine (DA) and norepinephrine (NE) systems influence cognitive deficits of schizophrenia patients, but one key enzyme is dopamine beta-hydroxylase (DBH), which converts DA to NE and whose activity and levels are under strong genetic control. This study examines the association of the 19bp insertion/deletion (Ins/Del) polymorphism in the 5′ flank of the DBH gene with cognitive deficits in first-episode schizophrenic patients (FEP). We assessed the cognitive function in 195 FEP and 304 healthy controls using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The 19bp Ins/Del polymorphism of DBH gene was genotyped. Our results showed that the allelic and genotypic frequencies of the 19bp Ins/Del polymorphism significantly differed between FEP and healthy controls (both p<0.05). Cognitive test scores were significantly lower in FEP than healthy controls on all scales (all p<0.001) except for the visuospatial/constructional index (p>0.05). Immediate memory abilities significantly differed by genotype (p<0.05) but not genotype×diagnosis. Immediate memory score was lower in FEP with DBH5′-Del/Del genotype (61.3±17.2) than those with DBH5′-Ins/Ins genotype (68.6±16.2; p<0.05). The 19bp Del allele was associated with poorer immediate memory performance than the Ins allele in FEP (p<0.05). However, healthy controls did not show any differences in cognitive function indices between the Ins and Del for either the allele or genotype of the 19bp Ins/Del polymorphism. Our findings suggest that the DBH5′-Ins/Del polymorphism may play a role in susceptibility to FEP. The DBH5′-Ins/Del polymorphism may also influence immediate memory in FEP. Moreover, FEP had poorer cognitive function than healthy controls in all examined cognitive domains except for the visuospatial/constructional index. [Copyright &y& Elsevier]

Abstract: Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [3H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n=6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium- and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex. [Copyright &y& Elsevier]

Background: Neural cell adhesion molecule (NCAM) is a glycoprotein and plays an important role in cell-cell adhesion, neural migration, neurite outgrowth, synaptic plasticity and brain development. We investigated the relationship between the serum NCAM concentration and cognitive deficit in first episode drug naïve schizophrenia (FES) patients.Methods: Thirty FES patients and thirty healthy controls were recruited for this study. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Cognitive functions were assessed by measurement and treatment research to improve cognition in schizophrenia (MATRICS) and consensus cognitive battery (MCCB). Serum levels of NCAM were determined by ELISA.Results: Schizophrenia patients had decreased serum NCAM concentrations than controls (-30%, p<0.001). Cognitive scores were significantly lower in FES patients than healthy controls (-34%, p<0.001). The NCAM concentrations were positively correlated with the total scores of MCCB (r=0.438, p=0.003). Multiple regression analysis confirmed that serum NCAM concentration was an independent contributor to MCCB total Scores.Conclusions: There were a close relationship between the serum NCAM concentrations and cognitive deficits in FES patients. Since NCAM has an important role in neurodevelopmental processes, these results support the neurodevelopmental dysfunction hypothesis of schizophrenia and suggest that an altered NCAM may be one of the risk factors for schizophrenia including cognitive deficits. [ABSTRACT FROM AUTHOR]