Modelling psychosis using DISC1 human induced pluripotent stem cells

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Schizophrenia and major mental illness are very common conditions whose aetiology is imperfectly understood and for which our treatments are only partially effective. They are known to be highly familial (genetic) and some genetic risk factors, including those affecteing the DISC locus, are sufficient to cause these disorders in a large proportion of individuals who carry them. It is also known that abnormalities of brain structure and function are closely linked to these genetic factors. The cellular mechanisms underlying these abnormalities and clinical disorder are however still unclear, largely becuase the human brain is inaccessable in vivo. However, it has recently become possible to study brain cells in vitro by reprogramming skin fibroblasts to become neurones and other neural cell types. We propose to study in vitro neural tissue derived from individuals with and without disease-causing translocation at the DISC locus. First, we will reprogramme their fibroblasts to become pluripotent stem cells, neural progenitors and neurons which will then be extensively validated and characterised. We will then examine how disease risk is conferred at a cellular level through a series of comparative studies of neural progenitor proliferation, neuronal morphology and physiology, and later by focussing specifically on the processes affected DISC1/2 and glutamate (NMDA) receptor expression.