Final Report Summary - DISC1 & AXOGENESIS (In vivo analysis of DISC1 function in synaptogenesis and axonal transport)
Schizophrenia is a highly heritable mental disorder that affects up to 1% of the world population. Multiple genes and environmental factors interact to cause the highly complex schizophrenic phenotype. Although a number of effective drug treatments currently exist, a clear mechanism for the drugs’ action has not been established, and the clinical outcomes remain variable. Eventually, a detailed understanding of the disease etiology at the cellular and molecular level will be required to develop a broader and more effective set of therapies. To this end, the most effective approach is perhaps the study of the physiological function of the proteins encoded by the genes identified to be associated with the disorder. Disrupted in Schizophrenia 1 (DISC1) is perhaps one of the best candidate susceptibility genes for schizophrenia. DISC1 was initially identified at the breaking point of a balanced t(1;11) chromosomal translocation that co-segregates with a broad diagnosis of psychiatric illness in a large Scottish family. Its linkage with schizophrenia has been successively confirmed by numerous studies. Given the great significance of DISC1 as a candidate gene for schizophrenia susceptibility, a great number of studies have focused on trying to elucidate its biological role in brain development and neuronal function. We have investigated the role of DISC-1 in vivo using the zebrafish retinotectal system as a model. In particular we focused on DISC1 function in anterograde and retrograde transport, synaptogenesis, axonal branches dynamics and synaptic function. The use of zebrafish to understand the molecular etiology of schizophrenic disorder should be seen as tool to dissect the molecular basis of this pathology, rather than a model of the disease in its entirety. Obviously zebrafish lack the complex behavioral repertoire present in humans and cannot be used to model this aspect of the disorder. Nevertheless, some of its unique features as a model organism make zebrafish an exciting system to analyze many biological processes at a molecular and cellular level in a whole living vertebrate. We have developed nove genetic approaches to disrupt in a temporal and spatial controlled manner the function of DISC1 in single neurons in the retinotectal neural circuit. Using in vivo imaging tools generated for this project we where able to analyze the role of DISC1 in axonal transport, synapses formation and function in vivo.