Coordination project

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Epileptic disorders are common and disabling conditions with a significant disease burden worldwide. Large-scale gene discovery combined with mechanistic studies have greatly accelerated our understanding of underlying causes. In the 1st funding period, our Research Unit (RU) has identified several new disease substrates for both rare and common genetic factors converging in the same pathways. Developing new analysis tools, such as paralog conservation or scaled phenotyping using human phenotype ontology, combined with experimental variant analysis in model systems, have revealed strong gene-, and gain-/loss-of-function-phenotype correlations with clinical relevance for management and treatment. Studies in animal models using a broad methodological spectrum across the RU, including in vitro and in vivo electrophysiological and imaging techniques, allowed comprehensive analyses that would not have been achievable by individual groups. These clearly mirror the added value of the collaborative effort with close interactions and teamwork throughout all projects of the RU. We have identified novel common pathophysiological principles, such as altered dendritic arborization and functional integration across different zebrafish and mouse models and developmental phenotypes with seizures occurring at well-defined time points. Since genetic findings initiated to create new mouse models now being available for further studies, and through the implementation of single-cell RNA sequencing (scRNA-seq) now feeding back into genetic studies to find new candidate genes, there is a continuous workflow in both directions. Finally, disentangling the mechanisms in various model systems from single cells to mice in vivo allowed us to translate these findings into effective treatment strategies, including re-purposing and mechanistic therapies in patients. Along these lines, our overarching goal will be to unravel genetically determined epileptogenic cascades at the intersection with the plastic environment of ongoing brain development and circuit maturation, and apply our findings toward therapeutic intervention. We will (i) elucidate the ‘missing heritability’ in both rare and common forms of genetic epilepsies using unprecedented case numbers with ~50,000 samples allowing us to approach the overall integrated burden of individual patients with both common and rare variants to determine the type and severity of their epilepsy, (ii) study epileptogenesis for newly identified genetic defects and in animal models generated during the 1st funding period to identify critical time windows for specific interventions, (iii) integrate scRNA-seq data from animal models in different stages of development with genetic data to identify epileptogenic key molecules and pathways, and (iv) leverage the acquired knowledge for translation into improved therapies including pharmacological treatment, RNA-targeting antisense and promoter interference systems.