Melbourne Veterinary School - Research Publications
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ItemCholinergic connectivity: it's implications for psychiatric disorders(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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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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ItemAMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder(ELSEVIER SCIENCE BV, 2012-02)BACKGROUND: Glutamate is thought to be involved in the pathophysiology of major depressive disorder and bipolar disorder; however, the molecular changes underlying abnormal glutamatergic signalling remain poorly understood. Whilst previous studies have suggested that the NMDA receptor may be involved in the pathophysiology of mood disorders, it is unclear whether the non-NMDA receptors are also involved. Therefore, we sought to examine whether the expression of the non-NMDA, ionotropic glutamate receptors, AMPA receptor and kainate receptor, is altered in mood disorders. METHODS: We used [3H]AMPA and [3H]kainate to measure the levels of AMPA and kainate receptor, respectively, in the anterior cingulate (BA 24) and dorsolateral prefrontal cortex (BA 46) from post-mortem CNS in 10 subjects with major depressive disorder, 10 subjects with bipolar disorder and 10 control subjects. RESULTS: A 20.7% to 27.7% increase in [3H]AMPA binding density was seen in BA 24 (p<0.05) but not BA 46 (p>0.05) in major depressive disorder compared to control levels. [3H]AMPA binding density was not changed in bipolar disorder in either BA 24 or BA 46 (p>0.05) compared to controls. [3H]Kainate binding was not changed in either BA 24 or BA 46 in either disorder compared to controls (p>0.05). LIMITATIONS: Small sample sizes (n=10) were used in this study. The subjects were not drug naïve. CONCLUSIONS: Our data suggests increased in AMPA receptor levels in the anterior cingulate are involved in the pathophysiology of major depressive disorder. This data has relevance for the development of new anti-depressant drugs targeted towards the AMPA receptors.
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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.