Characterising mice syntenic for human 16p11.2 duplications or deletions in relation to schizophrenia and autism

心理健康对社会的影响是巨大的。据估计，自闭症谱系障碍（ASD）影响约0.6%的人口，占全球疾病负担的0.3%，而精神分裂症影响约1%的人口，被认为是全球残疾的第九大原因。ASD的有效药物治疗并不存在，而目前用于精神分裂症的药物具有许多令人不快的副作用，仅对阳性症状有效，并且在约30%的患者中无效;因此大多数患者仍然慢性受损。迫切需要新的和改进的治疗方法。我们对与精神分裂症相关的神经生物学功能障碍有了一些了解。特别是前额叶皮层，一个参与思考和计划的区域，在患有这种疾病的患者中表现出代谢活动减少，沿着细胞的损失，这些细胞含有相对罕见的蛋白质，称为小清蛋白，并使抑制性大脑化学递质GABA。自闭症的情况就不那么清楚了，这可能反映了症状严重程度的巨大差异。然而，已知不同的大脑区域（皮层的部分）相互交流的能力存在缺陷。遗传和环境因素会增加患自闭症和精神分裂症的风险。与这些疾病有关的环境风险因素似乎是不同的，但有趣的是，一些基因现在被认为与这两种疾病有关。在少数情况下，存在一种相互关系，即一组基因的丢失会增加一种疾病的风险，而该组基因的获得会增加另一种疾病的风险。在自闭症和精神分裂症之间没有任何明显相反的关系的情况下，对这些基因的研究在疾病病因学方面具有潜在的高度信息性。包含29个基因的16号染色体片段就是这样一个区域：丢失一个拷贝会显著增加患自闭症的风险，而获得同一片段的额外拷贝会显著增加患精神分裂症的风险。小鼠已经被改造为复制这些基因缺失和复制。在这个项目中，我们将确定小鼠的这些遗传变化如何影响大脑功能的各个方面，这些方面类似于患者表现出损伤的参数。我们将监测认知能力，大脑区域代谢活动（包括前额叶皮层），大脑网络连接，以及受影响大脑区域表达的关键蛋白质（包括小清蛋白）。利用这些小鼠模型，我们将对这些疾病的原因有新的认识。此外，这些研究将验证小鼠品系作为未来药物开发的有用模型。积极的发现应该有相当大的影响，了解这些疾病和改善他们的治疗。

The impact of mental health on society is enormous. It is estimated that autism spectrum disorders (ASD) affect around 0.6% of the population and account for 0.3% of the global burden of disease, while schizophrenia affects ~1% of the population and is considered to be the 9th leading cause of disability worldwide. Effective pharmacological treatments for ASD do not exist, while current medications for schizophrenia have many unpleasant side-effects, are only active against the positive symptoms, and are ineffective in around 30% of patients; hence the majority of patients remain chronically impaired. New and improved treatments are urgently required. We have some understanding of the neurobiological dysfunction associated with schizophrenia. In particular, the prefrontal cortex, an area involved in thought and planning, shows reduced metabolic activity in patients with the disease, along with the loss of cells that contain a relatively rare protein called parvalbumin and make the inhibitory brain chemical transmitter GABA. The picture is less clear with autism, possibly reflecting great variability in symptom severity. However, there are known to be deficits in the ability of different brain regions (parts of the cortex) to communicate with each other. Genetic and environmental factors contribute to the risk of developing both autism and schizophrenia. The environmental risk factors implicated in these diseases seem to be distinct, but intriguingly, some genes are now thought to be linked to both diseases. In a few cases, there is a reciprocal relationship, where loss of a set of genes increases risk of one disease, while gain of the set of genes increases risk of the other. In the absence of any overtly opposite relationship between autism and schizophrenia, the study of such genes is potentially highly informative in terms of disease aetiology. A segment of chromosome 16, encompassing 29 genes, is one such region: the loss of a copy increases the risk of autism dramatically, while gain of an extra copy of this same segment markedly increases risk of schizophrenia. Mice have been engineered to reproduce these genetic deletions and duplications. In this project we will determine how these genetic changes in mice affect aspects of brain function that are analogous to parameters where patients show impairment. We will monitor cognitive performance, brain regional metabolic activity (including the prefrontal cortex), brain network connectivity , and also key proteins (including parvalbumin) expressed in affected brain regions. Using these mouse models, we will gain new insight into the causes of these diseases. In addition, these studies will validate the mouse strains as useful models for future drug development. Positive findings should have considerable impact for understanding these diseases and improving their treatment.