Pheno-connectomics of human neurodevelopmental diseases

ended

There is much we don't know about how neurons connect in our brains, but we know that their connectivity is essential for brain function in health and disease. Many psychiatric diseases coincide with the miswiring of the brain: to understand these, we need to know how neurons connect in each condition. I will develop a new approach to map single-cell synaptic connectivity, and use it to study joint connectome & transcriptome changes in an established monogenic autism spectrum disorder (ASD) organoid model. Change in synaptic connectivity is a key feature of ASDs, such as Rett-syndrome, which is caused by a mutation of the epigenetic regulator, MECP2. To understand how Rett-syndrome manifests on both transcriptional and connectivity levels, I will compare healthy & MECP2-KO human cortical organoids. I will combine single-cell mRNA sequencing and transsynaptic viral tracing techniques with barcoding. I will subsequently develop the required computational analysis entailing multi-omics integration and network analysis, and use statistical reconstructions to study the global properties of the organoid connectome. In essence, the project aims at four advances: Technology: – Develop a connectome-by-sequencing assay to chart synaptic networks of thousands of neurons. Basic biology: – Find out how many, and what kind of connections do single neurons form? – Do ‘lonely’ neurons have a different transcriptome than highly connected ones? Concept: – Introduce single-cell connectomics as a phenotype (pheno-connectomics) to understand diseases, and find their earliest manifestation. Disease mechanism: – How genetic defects affect gene expression, and concurrently the connectome? – Are all cell types affected the same way?