Psychiatry - Research Publications
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ItemBiomarker investigations related to pathophysiological pathways in schizophrenia and psychosis(FRONTIERS MEDIA SA, 2013-06-26)Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and protein. However, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA (miRNA) dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations.
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ItemAberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue(SPRINGERNATURE, 2016-01-19)Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.
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ItemA Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings(HINDAWI LTD, 2015)Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems.
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ItemSELENBP1 expression in the prefrontal cortex of subjects with schizophrenia(SPRINGERNATURE, 2015-08-04)Selenium binding protein 1 (SELENBP1) messenger RNA (mRNA) has previously been shown to be upregulated in the brain and blood from subjects with schizophrenia. We aimed to validate these findings in a new cohort using real-time PCR in Brodmann's Area (BA) 9, and to determine the disease specificity of increased SELENBP1 expression by measuring SELENBP1 mRNA in subjects with major depressive disorder and bipolar disorder. We then extended the study to include other cortical regions such as BA8 and BA44. SELENBP1 mRNA was higher in BA9 (P = 0.001), BA8 (P = 0.003) and BA44 (P = 0.0007) from subjects with schizophrenia. Conversely, in affective disorders, there was no significant difference in SELENBP1 mRNA in BA9 (P = 0.67), suggesting that the upregulation may be diagnosis specific. Measurement of SELENBP1 protein levels showed that changes in mRNA did not translate to changes in protein. In addition, chronic treatment of rats with antipsychotics did not significantly affect the expression of Selenbp1 in the cortex (P = 0.24). Our data show that elevated SELENBP1 transcript expression is widespread throughout the prefrontal cortex in schizophrenia, and confirm that this change is a consistent feature of schizophrenia and not a simple drug effect.
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ItemMuscarinic M1 receptor sequence: Preliminary studies on its effects on cognition and expression(ELSEVIER, 2012-06)It has been reported that people with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism of the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test than those who are heterozygous. We investigated whether CHRM1 sequence is associated with impaired executive function, a common problem in schizophrenia. We sequenced the CHRM1 using peripheral DNA from 97 people with schizophrenia who completed the Wisconsin Card Sorting Test, a verbal fluency test and the National Adult Reading Test. Clinical severity was assessed using the Positive and Negative Syndrome Scale. To determine whether CHRM1 sequence affected receptor expression, we used post-mortem data, from another cohort, to investigate associations between CHRM1 sequence and mRNA levels. On the Wisconsin Card Sorting Test, 267C/C participants with schizophrenia made more perseverative errors (p<0.05) and perseverative responses (p<0.05) than 267C/A participants. Genotype had no effect on verbal fluency (p=0.8) or National Adult Reading test (p=0.62). Cortical CHRM1 mRNA levels did not vary with gene sequence (p=0.409). The clinical study supports the proposal that CHRM1 sequence is associated with alterations in some aspects of executive function. However, the post-mortem study indicates this is not simply due to altered expression at the level of mRNA, suggesting this sequence alteration may affect the functionality of the CHRM1.
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ItemDifferent changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders(NATURE PUBLISHING GROUP, 2013-07)The growing body of evidence implicating tumor necrosis factor-α (TNFα) in the pathophysiology of psychiatric disorders led us to measure levels of that protein in the cortex of subjects with major depressive disorders (MDD). Having reported an increase (458%) in the levels of the transmembrane (tmTNFα), but not the soluble (sTNFα), form of the protein in Brodmann's area (BA) 46, but not 24, in people with the disorder, we decided to examine additional components of TNFα-related pathways in the same regions in people with MDD and extend our studies to the same cortical regions of people with schizophrenia (Sz) and bipolar disorders (BD). Using postmortem tissue, western blots and quantitative PCR, we have now shown there is a significant increase (305%) in tmTNFα in Brodmann's area 24, but not 46, from subjects with BD, and that levels of the protein were not altered in Sz. Levels of sTNFα were not altered in BD or Sz. In addition, we have shown that levels of TNF receptor 1 (TNFR1) mRNA are increased in BA 24 (53%) and BA 46 (82%) in people with Sz, whereas levels of TNFR2 mRNA was decreased in BA 46 in people with mood disorders (MDD=-51%; BD=-67%). Levels of proteins frequently used as surrogate markers of neuronal, astrocytic and microglia numbers, as well as levels of the pro-inflammatory marker (interleukin 1β), were not changed in the cortex of people with mood disorders. Our data suggest there are differential changes in TNFα-related markers in the cortex of people with MDD, BD and Sz that may not be related to classical inflammation and may cause changes in different TNFα-related signaling pathways.
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ItemΒ-actin does not show the characteristics of a reference protein in human cortex(WILEY, 2019-01)Levels of a reference protein must be the same as a proportion of total protein in all tissues and, in the study of human diseases, cannot vary with factors such as age, gender or disease pathophysiology. It is increasingly apparent that there may be few, if any, proteins that display the characteristics of a reference protein within the human central nervous system (CNS). To begin to challenge this hypothesis, we used Western blotting to compare variance in levels of the "gold standard" reference protein, β-actin, in Brodmann's area 9 from 194 subjects to variance of total transferred protein measured as intensity of Ponceau S staining. The coefficient of variance of sum intensity measurements for β-actin levels across all donors was 47% compared to 24 and 27% for the sum intensity of Ponceau S staining measured using two different detection techniques. These data strongly suggest that the level of β-actin, proportional to total protein, is not constant in human cortex which raises further doubt about the use of reference proteins to normalise data in human CNS studies. Considering our data, we suggest an alternative approach to presenting data from Western blotting of human CNS.
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ItemmRNA expression of the P5 ATPase ATP13A4 is increased in Broca's Area from subjects with schizophrenia.(Taylor & Francis, 2018-12-03)OBJECTIVE: ATPase Type 13A4 (ATP13A4) is a cation-transporting, P5-type ATPase that has been implicated in neurodevelopmental disorders. Our recent microarray study reported a significant increase in ATP13A4 mRNA levels in Brodmann's Area (BA) 9 in subjects with schizophrenia compared to controls. Following this discovery we have sought to determine whether ATP13A4 expression was altered in other regions of the CNS that are affected in schizophrenia. METHODS: Quantitative PCR was used to measure the levels of ATP13A4 in BA 44 and BA 8, collected post-mortem, from 30 subjects with schizophrenia and 30 non-psychiatric control subjects. To address the potential confound of antipsychotic medication on our data, qPCR was used to measure Atp13a4 levels in rats treated with haloperidol. RESULTS: There was a 2.6-fold increase in ATP13A4 expression (p < 0.001) in BB 44 from subjects with schizophrenia. Results from BA 8 were less clear. ATP13A4 levels were not affected by antipsychotic treatment. CONCLUSIONS: Our findings suggest ATP13A4 is involved in the pathophysiology of schizophrenia. The increase in ATP13A4 contrasts genetic studies that report ATP13A4 gene deletions in patients with schizophrenia. A greater understanding of the function of ATP13A4 in the CNS may lead to improved treatment strategies for the symptoms of schizophrenia.
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ItemNon-Coding RNA as Novel Players in the Pathophysiology of Schizophrenia.(MDPI AG, 2018-04-12)Schizophrenia is associated with diverse changes in the brain's transcriptome and proteome. Underlying these changes is the complex dysregulation of gene expression and protein production that varies both spatially across brain regions and temporally with the progression of the illness. The growing body of literature showing changes in non-coding RNA in individuals with schizophrenia offers new insights into the mechanisms causing this dysregulation. A large number of studies have reported that the expression of microRNA (miRNA) is altered in the brains of individuals with schizophrenia. This evidence is complemented by findings that single nucleotide polymorphisms (SNPs) in miRNA host gene sequences can confer an increased risk of developing the disorder. Additionally, recent evidence suggests the expression of other non-coding RNAs, such as small nucleolar RNA and long non-coding RNA, may also be affected in schizophrenia. Understanding how these changes in non-coding RNAs contribute to the development and progression of schizophrenia offers potential avenues for the better treatment and diagnosis of the disorder. This review will focus on the evidence supporting the involvement of non-coding RNA in schizophrenia and its therapeutic potential.
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ItemGlutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders(BAISHIDENG PUBLISHING GROUP INC, 2018-06-28)Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter (EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.