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Molecular stress signalling in human psychiatric illness and cortical development: the glucocorticoid receptor and its chaperones
Citation
Sinclair, D, Molecular stress signalling in human psychiatric illness and cortical development: the glucocorticoid receptor and its chaperones (2011) [PhD]
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Abstract
Developmental exposure to stress and dysregulation of the hypothalamic-pituitaryadrenal (HPA) axis have been implicated in the onset and course of schizophrenia and
bipolar disorder. It is not known to what extent molecular changes in cortical stress
response pathways are present in psychotic illness. Promising targets for investigation
of stress-related molecular pathology in psychiatric illness are the glucocorticoid
receptor (GR) and its chaperones, which together mediate cellular stress responses
and control HPA axis activation. In this thesis I explored the abundance, variety,
localisation and function of GR mRNA variants and protein isoforms in the prefrontal
cortex, a region displaying substantial pathology in psychiatric illness. Post-mortem
tissues from two psychiatric illness cohorts (schizophrenia, bipolar disorder and
control cases) and a developmental cohort (cases from 1 month – 49 years) were
used. I demonstrated, for the first time, extensive GR mRNA deficits in schizophrenia
in the dorsolateral prefrontal cortex (DLPFC), involving multiple alternative 5’ GR
mRNA transcripts. Similar, but less extensive, GR mRNA deficits were seen in
bipolar disorder in the DLPFC. Two genetic variants in the GR gene (NR3C1) were
associated with altered GR mRNA levels in the DLPFC. In a second prefrontal
cortical area, the orbitofrontal cortex (OFC), fewer deficits of GR mRNA expression
were observed. However, in both prefrontal cortical regions, I identified a truncated,
functional GRα protein isoform, putative GRα-D1, which was significantly increased
in both schizophrenia and bipolar disorder. I also identified abnormalities of stress
signalling co-factors FKBP5 and BAG1 in both disorders, highlighting that molecular
stress signalling abnormalities in psychosis may extend beyond GR. Across cortical
development, I observed dynamic patterns of GR expression and cellular localisation,
suggesting the existence of possible windows of heightened stress vulnerability
across the lifespan. Age- and gender- related changes in stress signalling chaperones
and co-factors across post-natal development were identified, suggesting a possible
mechanism underlying gender differences in stress responsiveness early in life.
Collectively, these studies of cortical GR stress signalling have provided comprehensive evidence of abnormalities in psychotic illness, and have illuminated
age- and gender-specific changes at life stages critical to the pathogenesis of
schizophrenia.
Item Details
Item Type: | PhD |
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Keywords: | stress, schizophrenia, human brain development |
Research Division: | Biomedical and Clinical Sciences |
Research Group: | Neurosciences |
Research Field: | Cellular nervous system |
Objective Division: | Health |
Objective Group: | Clinical health |
Objective Field: | Treatment of human diseases and conditions |
UTAS Author: | Sinclair, D (Dr Duncan Sinclair) |
ID Code: | 143858 |
Year Published: | 2011 |
Deposited By: | Wicking Dementia Research and Education Centre |
Deposited On: | 2021-04-07 |
Last Modified: | 2021-04-08 |
Downloads: | 0 |
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