[Truncated] Schizophrenia is severe neuropsychiatric disease oftencharacterised by marked delusions, hallucinations and abnormalities incognition. However, some abnormal traits found in schizophrenia are notstrictly diagnostic, but may be considered as biomarkers: biologically basedmeasurements indicative of disease state and/or progression. This thesisdemonstrates several applications of biomarkers to examine the aetiology andneurobiology of schizophrenia.
Genes and alterations in neurodevelopment play importantroles in schizophrenia. The potential roles of two neurodevelopmentallyimportant genes were investigated, ephrin-A2 and ephrin-A5, which are expressedin multiple regions involved with schizophrenia. The role of these genes wasexamined in knock-out (KO) mice models using schizophrenia biomarkers utilisingelectrophysiology (auditory brainstem responses), behavioural testing (prepulseinhibition of the acoustic startle reflex) and behavioural monitoring(circadian profiling). Ephrin-A2 and ephrin-A5 KO mice exhibited alteredauditory sensitivity, indicating that these proteins have an important role in auditorybrainstem development. Lack of expression did not disrupt the commonly usedschizophrenia biomarker, prepulse inhibition of the acoustic startle reflex.However, KO resulted in changes of startle size and latency, indicating thatephrin-A2 and ephrin-A5 play a role in neuromotor function. There was littleevidence for circadian involvement of these genes. In summary, the thesis showsthat ephrin- A2 and ephrin-A5 are not consistently associated with biomarkersin schizophrenia, but do have previously undescribed roles in hearing andneuromotor development.
Many environmental risk factors exist for schizophrenia, many of which appear to be related to early life stress. The thesis examined the hypothesis that neonatal stress leads to schizophrenia-like biomarkers by observing the effects of repeated neonatal injections of the synthetic glucocorticoid dexamethasone on rat adult phenotypes. The battery of tests used a variety of schizophrenia biomarkers including: auditory evoked potentials, EEG, behavioural testing and gene expression analyses. The results revealed a lack of schizophrenia-like traits. Furthermore, in several domains such as amphetamine sensitivity and stress reactivity, neonatal dexamethasone exposure demonstrated phenotypes opposite to those found in schizophrenia.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2015|