Impairment Of Neural Plasticity And Adaptive Representations By Genetic Risk Factors For Schizophrenia

精神分裂症是一种严重的神经发育障碍，最常见于青少年晚期/20岁出头，影响约1%的人口。这种疾病给患者、护理人员和卫生服务部门带来了沉重的负担，患者的高自杀率（约7%）和NHS在成人心理健康方面的支出约占30%。仅在英格兰，精神分裂症的经济成本估计为120亿英镑/年。心理治疗本身并不是一种有效的治疗方法，尽管有一些有效的药物，但那些被许可的药物往往耐受性差。因此，有一个很大的未满足的需求，以确定新的治疗方法。为了开发新的治疗方法，我们需要了解精神分裂症的潜在生物学原因。一个强有力的指南来自对精神分裂症患者的大型研究中的基因突变的分析，其中最近的一项研究是今年发表的，突出了10个个体基因，这些基因的破坏赋予了患上这种疾病的高风险。在这些基因中，有4个与突触功能和神经元连接的适应能力直接相关，为潜在的生物学原因提供了强有力的指导。然而，目前尚不清楚这些基因突变是否会导致类似的生物破坏。这对于确定治疗策略所需的个性化程度非常重要。神经元分支中的钙信号驱动突触适应，对神经元功能的微小扰动非常敏感。我们最近的数据表明，与精神分裂症风险相关的个体基因的破坏会导致这些钙信号的共同破坏。由于突触适应是认知过程（如记忆）的基础，我们进一步提出这会导致认知障碍。我们的跨学科计划提供了一种整体方法来测试这一假设，使用完整脑组织中神经元的高分辨率钙成像，这些神经元携带复制精神分裂症中发现的特定基因突变。我们将把这些突变引入小鼠，以及从接受脑手术的患者身上取出的人类神经元。我们将通过评估小鼠的认知功能，将神经元钙信号的中断与行为联系起来。基于我们的发现，我们还将探索潜在的药物靶点来拯救神经元钙信号。使用取自不同发育阶段的小鼠和人类的组织，我们还将发现这些生物学破坏是否发生在精神病和诊断出现之前，最常见的是在青少年后期/成年早期，这可能导致精神分裂症新的早期生物学体征的发展。总体而言，该计划旨在开发一个平台，以了解精神分裂症中发生的认知过程的潜在生物学干扰，并探索扭转这些干扰的机制。将来，我们可以测试与精神分裂症相关的其他基因突变，但我们也可以探索其他具有强烈遗传风险因素的精神疾病，如自闭症，是否也表现出神经元钙信号的破坏。事实上，许多与精神分裂症有关的基因也与自闭症有关，找出为什么特定的突变会导致这种或那种疾病是很重要的。

Schizophrenia is a severe neurodevelopmental disorder, most commonly diagnosed in late teens/early 20s, that affects ~1% of the population. The disorder places a major burden on sufferers, carers and health services evidenced by high suicide rates in sufferers (~7%) and consuming ~30% of NHS spending on adult mental health. In England alone, the economic cost of schizophrenia is estimated at £12 billion/year. Psychotherapy is not an effective treatment on its own and although there are some effective medications, those that are licenced are often poorly tolerated. Therefore, there is a large unmet need to identify new treatments.To develop new treatments, we need to understand the underlying biological causes of schizophrenia. A powerful guide comes from analysis of genetic mutations in large studies of people with schizophrenia, the most recent of which, published this year, highlight 10 individual genes whose disruption confers a high risk of developing the disorder. Of these genes, 4 are directly associated with synaptic function and the ability for neuronal connections to adapt providing a strong guide to the underlying biological causes. However, it is not clear whether these genetic mutations cause similar biological disruptions. This is important for determining what degree of personalisation is required for therapeutic strategies.Calcium signals in the branches of neurons drive synaptic adaptations and are incredibly sensitive to small perturbations in neuronal function. Our recent data suggest that disruption to individual genes associated with risk for schizophrenia cause a common disruption to these calcium signals. Since synaptic adaptations are fundamental to cognitive processes such as memory, we further propose that this leads to cognitive impairment. Our interdisciplinary programme provides a holistic approach to test this hypothesis using high-resolution calcium imaging of neurons in intact brain tissue that carry specific genetic mutations replicating those found in schizophrenia. We will introduce these mutations into mice, and into human neurons removed from patients undergoing brain surgery. We will link disruptions to neuronal calcium signals through to behaviour, by assessing cognitive function in mice. Based on our findings, we will also explore potential drug targets to rescue neuronal calcium signalling. Using tissue taken from mice and humans at different developmental stages we will also discover if these biological disruptions occur in advance of the emergence of psychosis and diagnosis, most commonly in late teens/early adulthood, which might lead to the development of novel early biological signs for schizophrenia. Overall, this programme aims to develop a platform to understand underlying biological disruptions to cognitive processes that occur in schizophrenia, and explore mechanisms to reverse them. In future we can test other genetic mutations associated with schizophrenia, but we can also explore whether other psychiatric disorders with strong elements of genetic risk such as autism also exhibit disrupted neuronal calcium signalling. Indeed, many genes associated with schizophrenia are also associated with autism and it will be important to find out why specific mutations lead to one disorder or another.