Melbourne Veterinary School - Research Publications

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Start date: 2012 × End date: 2012 × Author: Gibbons, Andrew ×

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    Muscarinic M1 receptor sequence: Preliminary studies on its effects on cognition and expression
    Scarr, E ; Sundram, S ; Deljo, A ; Cowie, TF ; Gibbons, AS ; Juzva, S ; Mackinnon, A ; Wood, SJ ; Testa, R ; Pantelis, C ; Dean, B (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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    AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder
    Gibbons, AS ; Brooks, L ; Scarr, E ; Dean, B (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.