Molecular Mechanisms in Schizophrenia Susceptibility

Schizophrenia is a severe mental illness which affects about 1 in every 100 people in Britain. Currently, little is known about how the brain is altered in schizophrenia. However, scientists have recently found genes that increase the chances of developing the illness. Researchers at the Institute of Psychiatry, Kings College London, are investigating how changes in these genes lead to changes in the human brain. They will first test to see if changes in these genes lead to differences in the level of the gene products in brain. They will then alter the level of these gene products in cells taken from the human brain to see how it affects these cells. This research will provide important new understanding of how changes in the brain lead to schizophrenia. This will help scientists develop new treatments for this devastating illness.

Schizophrenia is a common and severe neuropsychiatric disorder. Neurobiological research has thus far provided only broad clues to aetiology and pathophysiology. The recent identification of susceptibility genes for schizophrenia provides an unparalleled starting point for unravelling the pathogenic mechanisms commonly involved in the disorder. It is widely hypothesised that variants within these genes increase risk for schizophrenia by altering the expression of the molecules they encode. This research will specifically test this hypothesis through highly stringent measures of relative allelic expression in human brain tissue. It will investigate which transcripts of these genes are affected by schizophrenia susceptibility variants and in which brain regions these effects are largest. These effects on gene expression will then be modelled in human neural cell lines using RNA interference. The cellular transcriptomic consequences of these perturbations will be assessed using whole genome expression arrays, in order to shed light on the molecular pathways and cellular processes by which they lead to increased susceptibility to schizophrenia. This research will significantly advance our understanding of schizophrenia disease mechanisms, with the potential of identifying novel therapeutic targets for the disorder.