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Authors & Affiliations
Frederik Nørby Friis Sørensen, Mirte Scheper, Rasmus Rydbirk, James D. Mills, Irina Korshunova, Eleonora Aronica, Konstantin Khodosevich
Abstract
Tuberous sclerosis complex (TSC) is a genetic disorder where many patients affected by the disease suffer from refractive epilepsy. To alleviate related symptoms, the patients must undergo surgery to resect the epileptogenic lesion. Obtaining this tissue and instantly flash freeze it provides a unique opportunity to gain insight to the pathogenesis of TSC.Thus, we embarked on an in-depth unbiased characterization of the transcriptomic landscape, cellular identify, and potential epileptogenic networks of frontal cortical tubers of pediatric TSC using snRNA-seq on resected epileptic tissue and comparing to sex and aged matched controls.Strikingly, we revealed that despite a highly disorganized cortical layer structure, virtually all layer-specific neuron types are present in cortical tubers, even rare subtypes. While the cell type specific defining molecular patterns being maintained in TSC, the general transcriptomic landscape is highly shifted in cortical tubers.Lastly, using a fluorescent in-situ hybridization approach we validated layer wise neuronal molecular patterns and compositional changes that occur in frontal cortical tubers of tuberous sclerosis.Thus, in this study we demonstrate that despite the highly disorganized cortical structure of TSC, all neuronal identities, which are present in the neurotypical cortex, are also present in TSC. This in turn reveals tremendous potential translational opportunities where modulation of neuronal migration could potentially recover circuit structure and ultimately lead to functional recovery and seizure amelioration.