Investigating potential subgroups within the schizophrenias: a study of cholinergic muscarinic receptor density and energy metabolism
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2016
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Melbourne Authors
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Psychiatry
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PhD thesis
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© 2016 Dr. Natalie Paige Thomas
Abstract
Background. A crucial step towards understanding the aetiology of schizophrenia (SCZ), and developing more effective diagnostic methods and treatments is to identify and characterise potential subgroups within the diagnosis. There is growing evidence to support the existence of biologically discrete subgroups; one such demonstration is a subgroup denoted muscarinic receptor deficient schizophrenia (MRDS). Making up 25% of the SCZ population, these subjects are separated due to their marked loss (75%) in [3H] pirenzepine binding (cholinergic muscarinic M1 receptor preferring ligand), measured in the dorsolateral prefrontal cortex (DLPFC) in post-mortem brain tissue. Having established the SCZMRDS subgroup in our laboratory, we have the ability to investigate the pathophysiology that presents within this discrete subgroup.
Study 1. Previous reports suggest lower [3H] pirenzepine and [3H] AF-DX 384 (muscarinic M2/ M4 receptor preferring ligand) binding in the caudate putamen (C.Pu) in SCZ subjects. However, it is not known if SCZMRDS subjects drive this decreased binding in the C.Pu, as they do in cortical regions. Therefore, to better understand the changes in muscarinic receptors in the C.Pu from SCZ subjects, and to delineate whether the SCZMRDS subgroup was identifiable in subcortical regions, we measured [3H] pirenzepine and [3H] AF-DX 384, and [3H] 4’DAMP binding in C.Pu from 40 SCZ subjects, 20 of which were SCZMRDS, 20 that were MRDSNON-MRDS, and 20 non-psychiatric controls (CTRL). These measures gave good estimation of muscarinic M1 receptor (CHRM1), CHRM2/4, and CHRM3 receptor levels, respectively. The level of [3H] pirenzepine binding was significantly lower in the C.Pu from subjects with SCZ when compared to CTRL (p < 0.0007). This was driven by the SCZMRDS group (p < 0.0001 relative to CTRL). The levels of [3H] AF-DX 384 binding was significantly lower in the C.Pu from SCZ subjects compared to CTRL (p < 0.0001); this was demonstrated more strongly in SCZMRDS subjects (p < 0.0001) than SCZNON-MRDS subjects (p < 0.001) when compared to CTRL subjects. No significant differences in [3H] 4’DAMP measures were shown. Collectively, the results demonstrated that the SCZMRDS subgroup had significantly different CHRM density profiles within the striatum, when compared to SCZNON-MRDS and CTRLS. These results reinforce the idea that SCZMRDS and SCZNON-MRDS cohorts are biochemically distinct with regards to CHRM biology. Within the cortex, reductions in CHRM density were observed predominately within the SCZMRDS cohort for all binding densities measured. Within the striatum however, reductions of [3H] AF-DX 384 binding were observed in both SCZMRDS and SCZNONMRDS subjects compared to CTRLS. This suggests that in terms of CHRM density, the striatum is more complicated compared to the cortex.
As CHRM1/4 agonist therapy represents a promising approach for treatment of both the positive and cognitive symptoms in people with schizophrenia, these results characterising discrete subgroups with regards to CHRM density are extremely relevant to CHRM drug therapy discussions.
Study 2. A recent microarray study by our group showed a significant decrease in the expression of Pyruvate dehydrogenase beta subunit (PDHß) in the dorsolateral prefrontal cortex (BA 9) from SCZMRDS subjects compared to SCZNON-MRDS subjects and controls. PDHß is the catalytic component of pyruvate dehydrogenase (PDH) that plays an essential role in its ability to convert pyruvate to acetyl-CoA, a rate-limiting step in the production of energy from glucose. Changes in levels of PDHß within the CNS could therefore have profound effects on energy utilisation in people with SCZ. The potential importance of such changes in PDHß led us to validate the microarray data. Quantitative PCR was used to measure levels of PDHß mRNA whilst Western blotting was used to measure levels of PDHß protein in BA 9 and the caudate in 40 SCZ subjects, 20 of which were SCZMRDS, and 20 non-psychiatric controls. Metabolite levels influenced by the rate of PDH activity were also measured in the caudate (pyruvate and lactate) in the same subjects. PDHß levels were not significantly different between SCZNON-MRDS or SCZMRDS and CTRL in BA9 at the levels of mRNA (p = 0.38), nor protein (p= 0.38). Within the caudate, protein levels were significantly different between the three groups (p < 0.05), where SCZNON-MRDS subjects demonstrated reduced levels compared to SCZMRDS and CTRLS. At the level of the metabolites, both pyruvate and lactate were increased in SCZNON-MRDS subjects compared to SCZMRDS and CTRL (p < 0.05, p < 0.01, respectively). Collectively, these results support the hypothesis that discrete biological subgroups in schizophrenia exist, segregating patients by the presence or absence of energy metabolism dysfunction, specifically PDH protein levels and the concentration of pyruvate and lactate within the caudate.
Careful dissection of schizophrenia subgroups is an important step in understanding the aetiology of the syndrome. My data contributes to our understanding of biological subgroups and may ultimately help establish necessary biological markers and appropriate treatments for the diverse patients living with schizophrenia.
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Keywords
schizophrenia, molecular psychiatry, cholinergic, energy metabolism, subgroups