Investigating genetic and environmental risk for psychosis mediated through L-Type voltage gated calcium channels

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Psychotic illnesses, such as schizophrenia and bipolar disorder, are associated with major changes in thought, perception and emotion. These conditions have a significant impact on sufferers and their families. Unfortunately we have made little progress for decades in improving treatment of these common conditions. This is because we have lacked an adequate understanding of their causes.Genetic risk factors are known to be important in the development of psychotic illnesses. Recent genetic advances have shown that variation in genes for voltage-gated calcium channels (VGCCs) is important in increasing risk for psychotic disorders. Environmental factors, such as early life stress, are also important in contributing to risk for the development of psychosis. We have recently found that early life stress affects the expression of VGCCs in the brain, suggesting that genetic and environmental risk factors may converge on VGCCs. This proposal aims to study the effects of genetic changes in VGCCs and how they may interact with early stress in order to better understand risk for psychotic illnesses. In the first part of the project we will investigate the effects of genetic changes in VGCCs (especially in a gene called CACNA1C) on the brain using rodent models. We will particularly focus on basic emotional learning mechanisms that are believed to go awry in psychotic disorders. In addition we will investigate the impact of genetic variation on molecular processes in the brain underlying these forms of learning. This work will give us a better understanding of the effects of genetic variation in CACNA1C.In the second part of the project we will investigate how an environmental risk factor for psychotic illnesses, namely early life stress, affects VGCCs. We have recently found that early life stress produces changes in the regulation of CACNA1C. This suggests that early life stress may impact on the brain in a way that converges with the effects of genetic changes in CACNA1C. To study this further we will investigate the molecular changes caused by early life stress. We will then compare these to effects caused by genetic changes in CACNA1C.Finally, we will directly investigate whether early life stress worsens the effects of genetic risk for psychosis. To do this we will use models in which we can control both the genetic and environmental exposures. We will investigate whether exposure to early life stress leads to a worsening of the molecular and behavioural changes produced by genetic variation in CACNA1C. This is important as we know relatively little about how genetic and environmental risk factors for psychosis interact, limiting our ability to intervene to prevent or treat these conditions.Overall this work will help us understand more about how genetic risk for psychosis affects the brain, and how genetic risk may interact with environmental risk. Such understanding will be essential for the development of new treatments for these disabling conditions.