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

研究 L 型电压门控钙通道介导的精神病的遗传和环境风险

• 批准号: MR/R011397/1
• 负责人: Jeremy Hall
• 金额: $ 97.39万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR011397%2F1
• 关键词: Investigating; genetic; environmental; risk; psychosis

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.

精神疾病，如精神分裂症和双相情感障碍，与思想、知觉和情感的重大变化有关。这些情况对患者及其家人有重大影响。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。这是因为我们对其病因缺乏足够的了解。众所周知，遗传风险因素在精神病的发展中起着重要作用。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障碍的风险方面起着重要作用。环境因素，如早期生活压力，也是导致精神病风险的重要因素。我们最近发现，早期生活应激影响大脑中VGCC的表达，这表明遗传和环境风险因素可能汇聚在VGCC上。这项建议旨在研究VGCC中基因变化的影响以及它们可能如何与早期应激相互作用，以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来研究VGCC的遗传变化(特别是一种名为CACNA1C的基因)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，我们还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风险因素，即早期生活应激，如何影响VGCC。我们最近发现，早期生活应激会导致CACNA1C调节的变化。这表明，早期生活压力对大脑的影响可能与CACNA1C基因变化的影响相一致。为了进一步研究这一点，我们将研究早期生活应激引起的分子变化。然后，我们将把这些与CACNA1C基因变化造成的影响进行比较。最后，我们将直接调查早期生活压力是否会恶化精神病的遗传风险。为了做到这一点，我们将使用可以控制遗传和环境暴露的模型。我们将调查早期生活应激是否会导致CACNA1C基因变异所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，限制了我们干预以预防或治疗这些疾病的能力。总而言之，这些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，以及遗传风险可能如何与环境风险相互作用。这种理解对于开发针对这些致残性疾病的新疗法是至关重要的。

项目成果

A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder.

CACNA1C 相关疾病的神经精神表型的横断面研究。

• DOI: 10.1016/j.pediatrneurol.2022.10.013
• 发表时间: 2023
• 期刊: Pediatric neurology
• 影响因子: 3.8
• 作者: Levy RJ

Social interaction following prepubertal stress alters prefrontal gene expression associated with cell signalling and oligodendrocytes.

青春期前压力后的社交互动改变了与细胞信号传导和少突胶质细胞相关的前额叶基因表达。

• DOI: 10.1038/s41398-022-02280-7
• 发表时间: 2022-12-16
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Moon, Anna L.;Clifton, Nicholas E.;Wellard, Natalie;Thomas, Kerrie L.;Hall, Jeremy;Brydges, Nichola M.
• 通讯作者: Brydges, Nichola M.

Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?

• DOI: 10.1016/j.biopsych.2021.10.018
• 发表时间: 2022-04-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Hall J;Bray NJ
• 通讯作者: Bray NJ

Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function.

• DOI: 10.1093/hmg/ddac105
• 发表时间: 2022-09-10
• 期刊: Human molecular genetics
• 影响因子: 3.5

SU13GENETIC VARIATION IN 'CALCIUM VOLTAGE-GATED CHANNEL SUBUNIT ALPHA1C (CACNA1C): INTERACTIONS WITH PREPUBERTAL STRESS AND IMPACT ON HIPPOCAMPAL DEPENDENT LEARNING

“钙电压门控通道亚基 ALPHA1C (CACNA1C) 中的 SU13 基因变异：与青春期前压力的相互作用以及对海马依赖性学习的影响

• DOI: 10.1016/j.euroneuro.2018.08.377
• 发表时间: 2019
• 期刊: European Neuropsychopharmacology
• 影响因子: 5.6
• 作者: Moon A