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

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Technical Report,01 Apr 2019,31 Mar 2020

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Baylor College of Medicine Houston United States

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Cortical tuber CT, the neuropathological hallmark of tuberous sclerosis complex TSC, is a major type of pediatric cortical dysplasia characterized by cortical dyslamination and the presence of dysplastic neurons such as balloon cells and cytomegalic neurons. It is generally believed that seizures associated with TSC arise from CTs, and preoperative localization and subsequent surgical removal of epileptogenic CTs often results in seizure freedom. A critical and unsolved question is what circuit components are present in CT that underlie its intrinsic epileptogenicity. While dysplastic cell types in CTs could be plausible culprits for seizure generation, we currently know little about how these abnormal cell types connect to each other and to more normal cell types to drive seizure activity. To this end, we are taking advantage of the wealth of epileptogenic CTs surgically resected at our institute, and propose to apply a high-throughput multipatch recording method up to 12 cells into brain slices prepared from these CTs to interrogate the connection abnormalities of CT local circuit. Massive, multi-patch recordings of distinct cell types from the same CT slices will enable unraveling the specific connectivity patterns of abnormal cell types characteristic of CTs, in addition to their intrinsic electrophysiological properties. The study will provide the first insights into circuit-level mechanisms underlying CT epileptogenesis, with the potential to identify the potential epileptic cell types. Once we identify candidates for the epileptic cell type, we will use a novel single-cell RNA-sequencing technique, Patch-seq, to derive their transcriptome to test if they have specific transcriptional profiles.

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  • Medicine and Medical Research

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