Schizophrenia is a chronic, common and debilitating illness which causes serious psychosocial impairments. Despite the adverse impact of schizophrenia on public health, progress in understanding its pathophysiology is frustratingly slow, which hinders discovery of new therapeutic mechanisms. The major factors that have impeded this exploration are the complex neurobiology of higher brain function and the ethical and practical difficulties of investigating the living brain. Thus, animal models are useful to investigate the pathophysiology and therapeutics of schizophrenia and related conditions. A useful animal model is an important tool to illuminate pathophysiology and signpost a target for treatment development. But animal models also have limitations and not all the phenotypic traits thought relevant to schizophrenia are expressed in all models. However, in-bred mouse strains have proved useful in the field of research into neurodevelopmental disorders. Therefore, in the first part of this thesis, behavioural and protein expression of C57BL/6N and 129 X1/SvJ mice were compared. The 129X1/SvJ strain, like the C57BL/6N strain, is a widely used background strain for behavioral research. Both 129X1/SvJ and C57BL/6N are routinely used in gene-targeting research. The results suggested that C57BL/6N mice mimic aspects of schizophrenia, at least in comparison with 129X1/SvJ mice. Therefore C57BL/6N mouse may have application in pre-translational screening of new treatments for schizophrenia. Oxytocin has been proposed as a possible treatment for neurodevelopmental conditions such as schizophrenia. However, there are gaps in the understanding of its therapeutic potential, in particular the extent to which it may have effects on non-social as well as social behaviors in both sexes. In the second part of the thesis, female and male C57BL/6N mice were used to study the effects of oxytocin on social and non-social behaviours relevant to schizophrenia. Oxytocin generally ‘improved’ behaviours analogous to those reported to be impaired in neurodevelopmental disorders, but effects were observed at different doses in each sex. The work here suggests oxytocin has potential for treatment of both social and non-social features of schizophrenia. Further research into the clinical application of this peptide hormone, which may in turn significantly extend treatment options across a spectrum of neurodevelopmental conditions, should be encouraged. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

Cognitive deficits are the single strongest predictor of the functional outcome in patients with schizophrenia. Current treatments are largely ineffective in improving cognitive impairments and promising pre-clinical research has mostly failed to translate clinically. Despite the advances provided by rodent models, the neurobiological basis of cognitive deficits in schizophrenia is poorly understood. Therefore, this thesis proposes a zebrafish model for studying cognitive impairments of schizophrenia. Although more evolutionarily distant to humans compared to the rat, the zebrafish has emerged as a popular vertebrate model of human disorders due to its genetic tractability, complex nervous system and elaborate behavioural repertoire. We investigated the effects of genetic alterations and neurodevelopmental disruption on behaviour and learning in zebrafish. Using both disc1 mutant lines and sub-chronic phencyclidine (PCP) on larvae from 6-10 dpf, we were able to assess behavioural changes as a function of developmental age. In particular, this thesis aimed to develop appropriate behavioural assays to assess zebrafish learning and executive function relevant to disorders seen in human patients with schizophrenia. It was possible to demonstrate robust learning across several domains, namely, reversal, classical avoidance and non-associative learning, alongside locomotor and anxiety-related behaviours. There were varied deficits associated with each of the two – genetic (disc1 gene mutation) and environmental (sub-chronic PCP) – manipulations, consistent with observations in rat research. Together, the research in this thesis demonstrates that a zebrafish model exhibits behaviour resembling that of mammalian models of schizophrenia and provides a foundation for the utility of zebrafish in examining cognitive impairments associated with schizophrenia.