Brain-enriched voltage-gated calcium channel isoforms: novel, genetically informed, therapeutic targets for psychiatric disorders

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The last few years have seen substantial progress in our understanding of the genetic basis of psychiatric illnesses such as schizophrenia and bipolar disorder (also known as manic depression). It is hoped, and often claimed, that this knowledge will lead to insights into the biology of these illnesses and new therapies. However, concrete examples of this argument are lacking. This research will begin to examine how we can move from genetic insights to new therapies by focussing on arguably the most promising set of molecules arising from the recent genetic studies: the voltage gated calcium channels (VGCCs).Calcium is an important signalling molecule and plays a key role in brain function. There is long-standing evidence that patients with bipolar disorder have abnormalities in calcium function. Recent genetic studies suggest that these abnormalities may be caused, in part, by alterations in the function of the VGCCs. These channels make attractive drug targets for treating bipolar disorder and other psychiatric disorders in which these channels are implicated. However, many different types of VGCCs are produced from a limited number of VGCC genes, and there is a lack of information about the precise types of VGCCs that are present in human brain, and how these channels are changed in psychiatric disorders and in those at higher genetic risk for these illnesses. Neither do we know how the critical brain VGCCs differ from those found elsewhere in the body. This grant will directly answer these three questions by identifying the VGCCs present and enriched in human brain, compared to other body tissues, and investigating how they are changed in association with genetic risk for psychiatric disorders, and in the diseases themselves. These studies will take advantage of a wealth of data that has already been collected, some of which we have unique access to. We will combine analysis of these existing datasets with cutting-edge experimental studies. Crucially, both our analyses and experiments will use human brain tissue. This is essential, because the number of different molecules that a single gene produces is much higher in humans than in others species, particularly in human brain, compared with other types of body tissue. Most of the studies that have investigated the types of VGCCs present in brain vs other tissues have either used animal tissue, or have looked at only a few people, which is unlikely to be sufficient to address this question. Indeed, our preliminary studies already demonstrate that much remains unknown about the types of VGCCs that are present in the human brain.The research described here will help us to understand the key brain-enriched types of VGCC to target to improve the treatment of psychiatric illnesses, as well as investigating how genetic variation in the VGCCs increases risk for developing them. More broadly, they will also provide a test of how we can begin to move from genetic findings to new treatments.