Recent genetic studies provide strong support for the gene Disrupted-in-Schizophrenia-1 (DISC1) in mental illness. Additional data obtained primarily by in vitro studies suggested that DISC1 may play a key role in neurodevelopment and cell signaling by interacting with other proteins, including nuclear distribution E-like (NUDE-L) protein and phosphodiesterase 4B. Despite recent advances in the study of DISC1 function, several critical issues remain unanswered. We propose to utilize a unique and reliable mouse model that we have established in our laboratory, which closely mimics the translocation observed in an affected family while preserving endogenous proteins levels, in order to facilitate a better understanding of the physiological contribution of DISC1 in normal and abnormal brain development and function in the context of psychiatric disorders. Our main goals are to a) facilitate a better understanding of the contribution of DISC1 in neurodevelopment, as well as in synaptic transmission and plasticity and b) test whether existing in vitro results can be validated in vivo in the mouse model we have established. Our analysis promises to provide valuable insights into the ways DISC1 increases the risk of psychiatric disorders and at the same time provide a well-characterized animal model that can be used to test further hypotheses and facilitate future drug development efforts.
