Our research is aimed at identifying what happens in the brain to predispose certain people to develop a major mental disorder (schizophrenia, bipolar disorder or recurrent major depressive disorder). It is well established that genetic inheritance strongly influences the chances of developing a major mental illness, and consequently we are studying the brain functions of genetic risk factors for major mental illness in order to understand disease mechanisms. We are focussing upon a gene called DISC1 because it is damaged by a chromosomal rearrangement (a translocation) that substantially increases the chances of developing schizophrenia, bipolar disorder or recurrent major depressive disorder in translocation carriers in a large family from Scotland. The protein product of this gene is known to be important for many aspects of brain development and function, and we aim to understand the mechanisms by which DISC1 regulates these processes, and how these mechanisms may be defective in psychiatric patients.

The DISC1 protein works together with several other proteins to perform its roles in the brain, including proteins specified by genes which are themselves potential genetic risk factors for major mental illness. We are investigating functions carried out by DISC1, together with a number of such proteins. One, called PDE4, acts together with DISC1 to control the amount of cAMP present within cells. cAMP is an important signalling molecule that specifies whether many cell functions are switched on or off, and we are investigating which of these cAMP-dependent functions, controlled by DISC1 and PDE4, may be defective in psychiatric patients, perhaps due to incorrect cAMP levels. We have also shown that DISC1 controls movement of mitochondria around neurons. Mitochondria are the ‘powerhouses’ of cells, providing the energy that is required to power most cellular functions. Proper brain function is critically dependent upon neurons being able to communicate with each other, and this process is powered by mitochondria which must be efficiently moved to the part of the neuron where they are required. Because neurons are extremely long and thin they are particularly sensitive to inefficient mitochondrial transport, and may be unable to communicate effectively as a result. We are investigating whether defective mitochondrial transport in neurons could increase the chances of developing a mental illness.

We are ‘reprogramming’ skin cells from psychiatric patients and their unaffected relatives to generate neurons ‘in a dish’ to use in our studies. These neurons will enable us to determine whether the processes we have identified as potentially of importance are defective in neural material derived from individuals carrying damaged copies of the genes we are studying. In this way we aim to identify brain mechanisms that influence the chances of developing a severe psychiatric disorder. We are grateful for the generosity of the people who have donated skin biopsies, without which we would be unable to access the neural material that is essential for this work.