Unravelling the regulatory code orchestrating neural circuit formation

Synapses form the basic building blocks in neural circuits mediating neuronal information transfer. Over the past years, individual genes with key roles in synapse formation have been identified, but our understanding of this process is still fragmentary. I hypothesize that an interplay between gene regulatory networks and cell-cell interactions coordinates the different stages of synapse formation, ranging from early cell-cell contact to synapse maturation and refinement. To test my hypothesis, I will focus on the well-characterized hippocampal mossy fiber (MF) synapse between the presynaptic dentate gyrus granule cells and postsynaptic Cornu Ammonis area 3 pyramidal neurons. I will integrate high-throughput multi-omics data covering different developmental time points. First, I will perform network reconstruction by integrating chromatin accessibility, transcriptome and translatome information to get insights on how gene regulation impacts synapse formation. Second, cell-cell communication and its downstream effect on intracellular signaling will be predicted and then validated. Finally, for hypotheses validation, CRISPR-mediated knockouts of candidate regulator genes will be performed, followed by transcriptome analysis. The analysis of this multi-modal atlas will not only enhance our knowledge of neural circuit formation, but also on how the dysregulation of synaptic connections can lead to neuronal diseases.