Clare Louise Beasley
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Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are debilitating psychiatric illnesses. Though the pathophysiology underlying each disorder is not yet understood, previous studies have suggested that altered immune function may play a role, with microglia, the brain’s resident immune cells, implicated in this process. A recent genetic association study and meta-analysis of microarray data indicated that dysregulation of CX3CR1, a microglial G-protein coupled receptor, may be associated with SCZ. Signaling between CX3CR1 and its neuronal ligand, fractalkine (CX3CL1), is proposed to mediate neuron-microglia interactions, recruiting microglia to synaptic sites and modulating changes in microglial activation status. However, it remains to be determined whether fractalkine is dysregulated in SCZ, BD, or MDD, or if fractalkine signaling is associated with microglial morphology and activation status, or synaptic density in these disorders. To this end, we quantified mRNA and protein expression of fractalkine, CX3CR1, and the disintegrin-like metalloproteinase 10 (ADAM10), involved in ectodomain shedding of fractalkine, in postmortem brain tissue from individuals with SCZ, BD, MDD and matched controls. We detected a significant decrease in fractalkine protein levels in SCZ relative to controls, suggesting fractalkine-CX3CR1 signaling may be disrupted in this disorder. Correlations were observed between fractalkine, CX3CR1, microglial measures and pre-synaptic protein levels.
Astrocyte dysregulation has been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD), however the exact nature of astrocytic alterations remains to be identified. I investigated whether levels of four astrocyte-specific proteins; glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase type 1L1 (ALDH1L1), vimentin, and excitatory amino acid transporter type 1 (EAAT1) are altered in SCZ and BPD. Immunohistochemical staining of ALDH1L1 and GFAP in human grey and white matter was also performed, and staining patterns compared qualitatively. Relative concentrations of GFAP, ALDH1L1, vimentin, and EAAT1 were assessed post-mortem in the dorsolateral prefrontal cortex in SCZ (n=35), BPD (n=34) and non-psychiatric control (n=35) groups by western blotting. The same proteins were also quantified in the cingulate cortex of rats administered the antipsychotics haloperidol and clozapine. Elevated levels of GFAP were observed in SCZ and BPD, when compared to controls. GFAP was also significantly increased in individuals with psychotic symptoms, when compared to those without. Vimentin, ALDH1L1 and EAAT1 levels did not differ between groups. Rats exposed to antipsychotics did not exhibit significant overall differences in any astrocytic protein, suggesting that increased GFAP in SCZ is not attributable to antipsychotic treatment. Our findings indicate that astrocyte pathology may be associated with psychotic symptoms. Lack of ALDH1L1 and vimentin variability, paired with increased GFAP levels, may imply that astrocyte numbers are unchanged but astrocytes are partially activated, or may indicate a specific dysregulation of GFAP. Immunohistochemical results suggest that ALDH1L1 may be a more reliable marker of astrocytes than GFAP in human grey matter.