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

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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.