Uncovering the role of the Arx gene in schizophrenia

Schizophrenia is a severe psychiatric disorder that affects approximately 200,000 Australians, and strikes at a young age, crimpling people for life. Current treatments for schizophrenia are anti-psychotic medications, which can improve some symptoms but have low compliance rates, and do not modify the biology of the disorder. This is largely due to a lack of understanding of the pathophysiology of schizophrenia. It is thought that a range of genetic and environmental risk factors that disrupt the developing brain culminate in the emergence of schizophrenia. These disparate risk factors, however, are likely to converge onto common signalling pathways, and thus a way forward is to identify key players along these common pathways that may then be targeted therapeutically. This project will test the hypothesis that the ARX gene is a key player in a common pathway disturbed in schizophrenia. Our recent clinical findings showed that genetic variants in the ARX gene are associated with schizophrenia. We also showed in a mouse model that an environmental risk factor for schizophrenia, prenatal exposure to infection, reduces Arx transcript expression. Thus, ARX may be a hub gene to a common biological pathway that is disturbed by many risk factors associated with schizophrenia. To test this new idea we will utilize two unique mouse models of Arx gene variants to determine, in a controlled environment, how Arx loss of function may cause cellular, network and behavioural disturbances relevant to schizophrenia. We will also assess molecular pathways that are disturbed across various genetic and environmental-induced mouse models of Arx loss of function to construct a biological pathway from molecules to cells to network function and behaviour that is disturbed across our models. This biological pathway will provide the framework for the identification of new molecules to target therapeutically to modify the biological course of schizophrenia and improve outcomes.