Modelling psychosis using DISC1 human induced pluripotent stem cells

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.

Schizophrenia and major mental illness are devastating conditions with a combined lifetime prevalence of over 10%. Whilst partially effective treatments are available, none are clearly disease modifying. Notwithstanding important insights provided by animal models there is a great and unmet need for further models of mental illness in order to develop more effective therapies. The t(1;11) translocation1, discovered in a large multiply affected Scottish family in very close contact with the Division of Psychiatry, is one of the strongest single genetic risk factors identified for major psychiatric disorders. Combining genetic discoveries with advances in reprogramming and resulting derivation of human induced pluripotent stem cell lines (hIPS) now allows human based disease models and several studies have demonstrated the feasibility of this approach for both neurological and psychiatric disorders.
The current proposal brings together major strengths in clinical psychiatry - specifically our ongoing and long-term study of the t(1;11) family, neurophysiology, molecular genetics, stem cell biology and in vitro disease modelling. We propose to develop a human in vitro model of psychosis by obtaining and then validating induced pluripotent stem cells, neural progenitors and forebrain neurons from individuals with and without the t(1;11) translocation. We will then conduct a number of comparative studies examining the effects of the translocation on neuronal structure and function, dendritic arborisation and spine density, before examining the effects on DISC1/DISC2 and NMDAR expression.

In addition to the academic beneficiaries of the proposed work, there are wider impacts that will involve patients, health care providers and the pharmaceutical industry.

1. Patients and health care providers
The fundamental objective of this clinically-driven research proposal is to further our understanding of disease biology in psychosis and to develop a platform to develop and test new and more effective drug treatments. The abnormalities discovered in cells from individuals in the current study are likely to lead to an improved understanding of disease biology, since they address the relevent tissue types in vivo and in human subjects for the first time. These insights will lead to more rational therapies targetted to the underlying abnoramlities in these individuals and therefore may lead to persoanlised treatments targetted to an individuals specific undrelying pathophysiology.

2. Pharmaceutical industry
By elucidating the cellular disease phenotype in the current proposal, this will immediately create a system whereby we can attempt to reverse these changes using existing therapies and new chemical entities. These cells may therefore enable a novel platform for drug developmentusing the most relevent tissue type, in vitro. Potentially this may increase the proportion of effective drugs that entre phase III trials and reduce the need for animal based studies.