Melbourne Veterinary School - Research Publications

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    Cholinergic connectivity: it's implications for psychiatric disorders
    Scarr, E ; Gibbons, AS ; Neo, J ; Udawela, M ; Dean, B (FRONTIERS MEDIA SA, 2013-05-03)
    Acetylcholine has been implicated in both the pathophysiology and treatment of a number of psychiatric disorders, with most of the data related to its role and therapeutic potential focusing on schizophrenia. However, there is little thought given to the consequences of the documented changes in the cholinergic system and how they may affect the functioning of the brain. This review looks at the cholinergic system and its interactions with the intrinsic neurotransmitters glutamate and gamma-amino butyric acid as well as those with the projection neurotransmitters most implicated in the pathophysiologies of psychiatric disorders; dopamine and serotonin. In addition, with the recent focus on the role of factors normally associated with inflammation in the pathophysiologies of psychiatric disorders, links between the cholinergic system and these factors will also be examined. These interfaces are put into context, primarily for schizophrenia, by looking at the changes in each of these systems in the disorder and exploring, theoretically, whether the changes are interconnected with those seen in the cholinergic system. Thus, this review will provide a comprehensive overview of the connectivity between the cholinergic system and some of the major areas of research into the pathophysiologies of psychiatric disorders, resulting in a critical appraisal of the potential outcomes of a dysregulated central cholinergic system.
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    Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue
    Lai, C-Y ; Lee, S-Y ; Scarr, E ; Yu, Y-H ; Lin, Y-T ; Liu, C-M ; Hwang, T-J ; Hsieh, MH ; Liu, C-C ; Chien, Y-L ; Udawela, M ; Gibbons, AS ; Everall, IP ; Hwu, H-G ; Dean, B ; Chen, WJ (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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    Autophagy has a key role in the pathophysiology of schizophrenia
    Merenlender-Wagner, A ; Malishkevich, A ; Shemer, Z ; Udawela, M ; Gibbons, A ; Scarr, E ; Dean, B ; Levine, J ; Agam, G ; Gozes, I (NATURE PUBLISHING GROUP, 2015-02)
    Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.
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    Studies on Prostaglandin-Endoperoxide Synthase 1: Lower Levels in Schizophrenia and After Treatment with Antipsychotic Drugs in Conjunction with Aspirin
    Dean, B ; Gibbons, A ; Gogos, A ; Udawela, M ; Thomas, E ; Scarr, E (OXFORD UNIV PRESS, 2018-03)
    BACKGROUND: Antipsychotic drugs plus aspirin (acetylsalicylic acid), which targets prostaglandin-endoperoxide synthase 1 (PTGS1: COX1), improved therapeutic outcomes when treating schizophrenia. Our microarray data showed higher levels of PTGS1 mRNA in the dorsolateral prefrontal cortex from subjects with schizophrenia of long duration of illness, suggesting aspirin plus antipsychotic drugs could have therapeutic effects by lowering PTGS1 expression in the cortex of subjects with the disorder. METHODS: We used Western blotting to measure levels of PTSG1 protein in human postmortem CNS, rat and mouse cortex, and cells in culture. RESULTS: Compared with controls, PTGS1 levels were 41% lower in the dorsolateral prefrontal cortex (P<.01), but not the anterior cingulate or frontal pole, from subjects with schizophrenia. Levels of PTGS1 were not changed in the dorsolateral prefrontal cortex in mood disorders or in the cortex of rats treated with antipsychotic drugs. There was a strong trend (P=.05) to lower cortical PTGS1 10 months after mice were treated postnatally with polyinosinic-polycytidylic acid sodium salt (Poly I:C), consistent with cortical PTGS1 being lower in adult mice after exposure to an immune activator postnatally. In CCF-STTG1 cells, a human-derived astrocytic cell line, aspirin caused a dose-dependent decrease in PTGS1 that was decreased further with the addition of risperidone. CONCLUSIONS: Our data suggest low levels of dorsolateral prefrontal cortex PTGS1 could be associated with the pathophysiology of schizophrenia, and improved therapeutic outcome from treating schizophrenia with antipsychotic drugs augmented with aspirin may be because such treatment lowers cortical PTGS1.