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

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.

Both genetic and environmental factors are known to be important in determining risk for the major psychotic disorders such as schizophrenia and bipolar disorder. Genomic studies have identified genetic variants in L-Type Voltage Gated Calcium Channels (L-Type VGCCs), particularly in the CACNA1C gene, as strongly associated with risk for both schizophrenia and bipolar disorder. Exome sequencing studies of schizophrenia have further confirmed an excess of mutations in L-Type VGCCs in patients compared to controls. This highlights the importance of understanding the molecular and behavioural consequences of mutations in L-Type VGCCs in relation to psychiatric disorders.

Calcium entry through L-Type VGCCs plays a critical role in controlling neuronal gene expression and neuronal plasticity. To characterise the specific effects of mutations in CACNA1C associated with psychosis we will investigate the effects of reduced CACNA1C gene dosage on behaviour and the control of gene expression. We will use a novel hemizygotic deletion rat model (Cacna1c +/-) that recapitulates the predicted effects of deleterious point mutations in CACNA1C associated with increased risk for schizophrenia. We will investigate the effects of reduced dosage of Cacna1c on behaviour, focussing on changes in associative learning, and on molecular pathways involved in the regulation of plasticity. We will also investigate the effects of early life stress on the molecular pathways regulated by Cacna1c, building on our recent finding that pre-pubertal stress results in sustained reductions in Cacna1c expression. Finally we will determine whether juvenile stress exacerbates psychosis-related behavioural phenotypes and changes in gene expression in Cacna1c hemizygous deletion animals.

This work will be an important step in advancing understanding of the mechanisms through which a major genetic risk locus for psychosis impacts on brain function and how genetic risk interacts with environmental risk.

Who will benefit?

In addition to the academic community (see Academic Beneficiaries) the main benefits will be to the pharmaceutical industry and clinicians. Greater understanding of the neural basis of psychotic disorders will also ultimately benefit patients, carers and wider society.

How will they benefit?

The major psychotic disorders place a huge burden on sufferers and society. Schizophrenia and bipolar disorder alone are estimated to together cost the UK economy more the £14 Billion per year. However there have been no fundamental advances in treatment for decades and whilst current treatments mask some of the symptoms of the disorder, they have significant side effects and are not effective for all patients. This lack in advance in treating psychotic disorders has arisen because of poor understanding of the fundamental aetiological factors causing these disorders.

Over the last decade major advances have been made in the genetics of schizophrenia and bipolar disorder, providing and important route to revealing the biological bases of these conditions. Genetic variation in voltage gated calcium channels (VGCCs) has been one of the most consistent signals from these genomic studies. However the current challenge is to translate genetics into neuroscience and better treatments for patients.

The VGCCs represent an important target for therapeutic development. Understanding the role of L-Type VGCCs in psychiatric risk may open up the possibility of developing new drugs or repurposing existing drugs for genetically stratified psychiatric populations. The work outlined in this proposal will provide more detailed molecular and behavioural characterisation of the effects of mutations in VGCCs, and will develop important models and metrics for future target validation in drug development. This is important as major international efforts are currently underway to develop new drugs targeting L-Type VGCCs (see letter of collaboration from the Structural Genomics Consortium and Sussex Drug Discovery Centre).

In addition to pharmaceutical development, our approach will also inform cognitive and psychological approaches to the management of psychotic disorders. Our proposal is grounded in behavioural psychology and in particular in associative learning theory. As such our work will increase understanding of how genetic risk factors for psychotic disorders can impact on specific types of learning and recall in patients, potentially informing the development of targeted psychological therapies for psychotic illnesses.

Our experiments will also provide a carefully controlled experimental investigation of the interaction of genetic vulnerability for psychiatric disorders with environmental risk factors. This is important as environmental factors like early stress have been convincingly shown to increase risk for psychosis however little is known about the means through which this increase in risk occurs. Greater understanding of the mechanisms of genetic and environmental interaction in risk for psychosis will be important the development of new interventions for the prevention and/or treatment of psychotic disorders.