Molecular stress signalling in human psychiatric illness and cortical development: the glucocorticoid receptor and its chaperones

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.