Deciphering Circuit-level Mechanisms Underlying Intrinsic Epileptogenicity of Cortical Tubers in TSC

Cortical tuber (CT), the neuropathological hallmark of tuberous sclerosis complex (TSC), is a major type of pediatric cortical dysplasia characterized by cortical dyslamination and constituent dysplastic cell types such as balloon cells and cytomegalic neurons. It is generally believed that seizures associated with TSC arise from CTs, and dysplastic cell types residing in CTs may be culprits to blame in seizure generation. However, we currently know little about how these abnormal cell types interact with other CT cells to drive seizure activity. By applying the multi-patch recording on slices prepared from surgically resected, epileptogenic CTs, we examine the connectivity of these dysplastic cell types to identify the potential epileptic cell types that may be critical for CT seizure generation. Single-cell RNA-sequencing is also applied to CT to uncover the transcriptomic landscape of CT at the level of cell types and to unravel genetic mechanisms underlying the unique phenotypes of abnormal cell types specific to CT. Our unbiased profiling of the cellular constituents of CTs from TSC cases so far uncovered the specific cellular populations in CT and suggests cytomegalic interneurons may be a critical player in seizure generation in CT.