Year

2015

Degree Name

Doctor of Philosophy

Department

Faculty of Science Medicine and Health

Abstract

Schizophrenia is a devastating disorder thought to evolve from a combination of environmental and genetic factors. Evidence suggests that the glutamatergic Nmethyl- D-aspartate receptor (NMDAR) may play a central role in the development of the disorder. The NMDAR, including the NR2B subunit of this receptor, is critical for normal brain development and has been implicated in the pathophysiology of schizophrenia, particularly the cognitive symptoms. It is hypothesised that developmental disruption to the NMDAR can cause a cascade of events resulting in altered developmental trajectories of other systems known to be involved in schizophrenia, such as the neuregulin (NRG), gamma-aminobutyric acid (GABA), and cannabinoid systems. The overall aim of this PhD thesis was to assess the potential role of the NR2B subunit in the pathophysiology and development of schizophrenia, with a particular focus on the examination of brain regions that mediate cognitive functions.

Collectively, this thesis has provided novel insights into the changes that occur in the NR2B subunit in schizophrenia, revealing for the first time that expression of NR2B is altered in the DLPFC and hippocampus of schizophrenia subjects, in a gender and hemisphere specific manner. These alterations may be related to cognitive symptoms experienced by patients, however further studies are required to determine this. This thesis also showed that perinatal NR2B antagonism causes some alterations to schizophrenia relevant systems including NR2B and NRG1 at adolescence, which could potentially make this animal model more vulnerable to further impacts at adolescence. It should be noted however, that this model did not cause widespread changes in systems (at least in terms of protein expression) relevant to the pathophysiology of schizophrenia. Finally, this thesis has identified that the developmental profiles of schizophrenia relevant systems, differs between the two genders (at least in a mouse model), highlighting the importance of considering this in the design of future studies.

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