The impact of schizophrenia-associated copy number variants on cortical network dynamics

精神分裂症(SZ)是一种致残性精神健康疾病，影响大约1%的英国人口。这种情况通常在青春期或成年早期出现，并与人们对现实的感知方式的变化(现实扭曲)和思维困难有关。SZ对患者及其家庭有重大的长期影响。不幸的是，在过去的几十年里，我们在改善这种疾病的治疗方面进展甚微。这是因为我们对精神分裂症的生物学病因缺乏足够的了解。最近对精神分裂症遗传基础的研究取得的重大进展为更好地了解SZ的生物学基础提供了希望，可能为早期诊断和治疗开辟新的途径。最引人注目的遗传学发现之一是，染色体结构的变化，即拷贝数变异(CNV)，会显著增加患精神分裂症的风险。因此，研究患有这些精神分裂症相关CNV的人(SZ-CNV)为理解与精神障碍风险相关的大脑变化提供了一条新的途径。在当前的提案中，我们旨在调查一些最常见的SZ-CNV如何影响大脑功能。我们假设，这些不同的SZ-CNV通过改变大脑皮层特定类型神经元的调节，对大脑功能具有共同的影响。我们进一步假设，这会影响不同神经元相互沟通的方式，导致现实扭曲和思维障碍。人脑很难直接研究，因为它很难接触到。因此，我们将结合不同的方法来研究SZ-CNV对大脑的影响。首先，我们将使用人脑成像来确定携带SZ-CNV的年轻人大脑活动和连接的变化。其次，我们将研究携带类似染色体变化的小鼠，以使我们能够比在人类身上进行更深入的研究。最后，我们将研究来自SZ-CNV患者的人类神经元放电和连接的变化。这些不同的方法将使我们能够建立起比任何单一技术都更完整的SZ-CNV影响大脑的方式。然而，跨这些方法比较和集成数据仍然是一项挑战。为了让我们能够做到这一点，我们将使用计算机建模来结合和整合我们的发现。我们随后将调查这些计算机模型预测SZ-CNV患者认知困难和精神症状的能力，包括精神分裂症的早期症状。这些模型的改进和测试将代表着一种提高我们对SZ-CNV病理效应的理解的手段。总体而言，这项工作将使我们能够进一步了解SZ-CNV如何影响脑功能和连接。我们将获得的见解将是朝着加强对精神分裂症的生物学原因的了解迈出的重要一步，目的是加强对这种疾病的早期诊断和治疗。

Schizophrenia (SZ) is a disabling mental health disorder that affects approximately 1% of the UK population. The condition typically has its onset in adolescence or early adulthood and is associated with changes in how reality is perceived (reality distortion) and difficulties in thinking. SZ has significant long-term impacts on the sufferer and their family. Unfortunately, over the past decades we have made little progress in improving the treatment of this disorder. This is because we lack adequate understanding of the biological causes of schizophrenia.Recent major advances in research into the genetic basis of schizophrenia now offer hope of better understanding of the biological basis of SZ, potentially opening up new avenues for early diagnosis and treatment. One of the most striking genetic findings has been that changes in chromosomal structure, referred to as Copy Number Variants (CNVs), can significantly increase risk for schizophrenia. Studying people with these schizophrenia-associated CNVs (SZ-CNVs) therefore offers a new route to understanding the brain changes associated with risk for the disorder.In the current proposal we aim to investigate how some of the most common SZ-CNVs affect brain function. We hypothesise that these different SZ-CNVs have common effects on brain function by altering the regulation of specific types of neurons in the brain cortex. We further hypothesise that this affects the way different neurons communicate with each, contributing to the reality distortion and thinking difficulties seen in the disorder. The human brain is difficult to investigate directly because of its inaccessibility. We will therefore combine different methods to investigate the impact of SZ-CNVs on the brain. Firstly, we will use human brain imaging to determine changes in brain activity and connectivity in young people carrying SZ-CNVs. Secondly, we will study mice carrying similar chromosomal changes to allow us to investigate in more depth than is possible in humans. Finally, we will study the changes in firing and connectivity in human neurons derived from patients with SZ-CNVs.These different methods will enable us to build up a more complete picture of the way these SZ-CNVs affect the brain than any single technique alone could. However, it remains a challenge to compare and integrate data across these methods. To allow us to do this we will use computer modelling to combine and integrate our findings. We will subsequently investigate the ability of these computer models to predict cognitive difficulties and psychiatric symptoms in people with SZ-CNVs, including the early symptoms of schizophrenia. The refinement and testing of these models will represent a means of improving our understanding of the pathological effects of SZ-CNVs.Overall, this work will enable us to advance understanding of how SZ-CNVs impact on brain function and connectivity. The insights we will gain will represent an important step towards improving understanding of the biological causes of schizophrenia, with the aim of enhancing the early diagnosis and treatment of the condition.