The influence of disease-associated mutations on dendritic and synapse structure

自闭症谱系障碍、精神分裂症或阿尔茨海默病等神经精神疾病的患病率很高，而且有很强的遗传成分。为了改进治疗策略，重要的是要了解定义特定疾病特征的潜在遗传结构、细胞底物和大脑回路之间的复杂相互作用。许多证据表明，在疾病的背景下，通过改变神经元主要通讯部位(称为突触)的大小和形状来控制神经元之间通讯的信号通路是失调的。有趣的是，在神经精神疾病中发现的许多风险基因都编码与神经元通讯有关的蛋白质。在拟议的研究范围内，我将重点研究其中一种蛋白质，即被认为参与这些信号通路的蛋白质。此外，在患者家属中发现了其氨基酸序列的变化，而在健康对照组中没有发现。然而，这些突变对完整大脑中神经元结构和功能的影响尚不清楚。我将使用最先进的遗传和成像工具来表达与疾病相关的变体，并分析它们对神经元和突触结构的影响。该项目将把疾病相关分子与完整大脑的结构变化联系起来，除了与疾病的相关性外，它还将分析基本大脑发育和连接的关键机制。

Neuropsychiatric disorders such as autism spectrum disorder, schizophrenia or Alzheimer’s disease have a high prevalence and a strong genetic component. To improve treatment strategies it is important to understand the complex interplay of the underlying genetic architecture, cellular substrates and brain circuits that define specific disease profiles. Much evidence indicates that the signaling pathways that control the communication between neurons by altering the size and the shape of their main communication sites, called synapses, are dysregulated in the disease context. Interestingly, many of the risk genes identified in neuropsychiatric disorders encode proteins that are implicated in neuronal communication. Within the scope of the proposed research, I will focus on one of these proteins, that is thought to participate in these signaling pathways. Furthermore, alterations in its amino acid sequence have been identified in patients’ families and not in healthy controls. However, the impact of these mutations on neuronal structure and function in the intact brain is not known. I will use state-of-the-art genetic and imaging tools to express the disease-associated variants and to analyze their impact on neuron and synapse structure. This project will link a disease-associated molecule with structural alterations in the intact brain and in addition to its relevance for disease it will also analyze key mechanisms underlying basic brain development and connectivity.