Grant: Fellowship: Bisby (Prize)

Schizophrenia is a chronic debilitating mental disorder afflicting 1% of the population worldwide. The symptoms of schizophrenia fall into three general categories including positive symptoms (hallucinations and delusions), negative symptoms (social withdrawal, blunted emotional affect) and cognitive deficits. Although the etiology is unknown, there is evidence to suggest that deregulation of a neurotransmitter called dopamine is involved. More specifically, one of the dopamine receptors, D2R has been suggested to be more functionally relevant given that all antipsychotic drugs are D2R antagonists and that intracellular signalling cascades that the D2R regulates have been implicated in schizophrenia. Recent developments have shown that intracellular signalling of the D2R is complex and that there are distinct signalling mechanisms (G-protein or beta-arrestin). What is unclear is the contribution these two signaling branches have in normal physiological and pathological manifestations of dopamine action. Thus, the current study addresses the role of the two distinct signalling mechanisms of the D2R. To accomplish this goal an in vivo (mice) approach will be used, where the D2R in the brain can only signal through one of the two signalling branches (G-protein or beta-arrestin). These mice will undergo a series of tests to investigate behavioural, cellular and morphological changes. Comparing these mice models will demonstrate the role of the individual D2R signalling branches and help to understand the potential contribution these D2R branches have in schizophrenia. By understanding the mechanism of how the dopamine system contributes to normal physiology and how its dysfunction contributes to schizophrenia will help to identify potential targets for therapeutic intervention.