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

精神疾病，如精神分裂症和双相情感障碍，与思想，感知和情感的重大变化有关。这些情况对患者及其家庭产生重大影响。不幸的是，几十年来，我们在改善这些常见疾病的治疗方面进展甚微。这是因为我们对这些疾病的成因缺乏足够的了解，而遗传风险因素在精神病的发展过程中是很重要的。最近的遗传学进展表明，电压门控钙通道（VGCC）基因的变异在增加精神病风险方面很重要。环境因素，如早期生活压力，也是导致精神病发展风险的重要因素。我们最近发现，早期生活压力会影响大脑中VGCC的表达，这表明遗传和环境风险因素可能会聚集在VGCC上。该提案旨在研究VGCC中遗传变化的影响，以及它们如何与早期压力相互作用，以便更好地了解精神疾病的风险。在该项目的第一部分，我们将使用啮齿动物模型研究VGCC（特别是称为CACNA1C的基因）的遗传变化对大脑的影响。我们将特别关注被认为在精神障碍中出错的基本情绪学习机制。此外，我们将研究遗传变异对这些学习形式背后的大脑分子过程的影响。这项工作将使我们更好地了解CACNA1C基因变异的影响。在项目的第二部分，我们将调查精神病的环境危险因素，即早期生活压力，如何影响VGCC。我们最近发现，早期生活压力会导致CACNA1C调节的变化。这表明，早期生活压力可能会以一种与CACNA1C基因变化的影响相一致的方式影响大脑。为了进一步研究这一点，我们将研究由早期生活压力引起的分子变化。然后我们将这些结果与CACNA1C基因改变所引起的效应进行比较。最后，我们将直接调查早期生活压力是否会影响精神病的遗传风险。为了做到这一点，我们将使用我们可以控制遗传和环境暴露的模型。我们将研究早期生活压力是否会导致CACNA1C遗传变异产生的分子和行为变化恶化。这一点很重要，因为我们对精神病的遗传和环境风险因素如何相互作用知之甚少，限制了我们干预预防或治疗这些疾病的能力。总的来说，这项工作将帮助我们更多地了解精神病的遗传风险如何影响大脑，以及遗传风险如何与环境风险相互作用。这种理解对于开发这些致残性疾病的新疗法至关重要。

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.