Deciphering Circuit-Level Mechanisms Underlying Intrinsic Epileptogenicity of Cortical Tubers in TSC
Abstract
Tuberous sclerosis complex (TSC) is complex genetic disorder often associated with pharmacoresistant seizures, autism, and intellectual disability, characterized by the presence of potato-like anatomical malformations in brain regions known as cortical tubers (CTs, the Latin name for potato) as well as tumors in other organs. Despite the clear involvement of mutations in either TSC1 or TSC2 gene in TSC, it remains to be elucidated how TSC1/TSC2 deficiency ultimately leads to pharmacoresistant seizures and other cognitive comorbidities. It is generally believed that seizures in TSC arise from potato-like CT brain structure, and preoperative localization and subsequent surgical removal of seizure-causing CTs often results in seizure freedom. CTs are characterized by the presence of bizarre-looking brain cells that are not present in the normal brain structure, which has led to the speculation that these cells are the “seizure-causing” cell types. To serve such a seizure-causing role, these cells may have unique intrinsic physiology properties capable of spontaneous firing acting as “pacemaker” and electrochemically interact in a unique way with other cells to spontaneously drive local brain cells and circuits into seizures. However, whether or not these abnormal cells are “seizure-causing” appears to an intractable question in the field, since rodent disease models do not develop bizarre-looking cells and abnormal anatomy in their brains characteristic of TSC. Fortunately, surgically resected, seizure-causing CTs could be kept alive outside the body for a long time, providing a precious opportunity to study the physiology of these abnormal cell types directly from human tissue. We are thus taking advantage of a wealth of surgically resected CTs tissue at our institutes, and apply the sensitive, high-throughput approach pioneered in basic research directly into this seizure-causing human tissue to address those seemingly intractable questions. We will perform a multi-modal analysis of these cell types in seizure-causing tissue, particularly how these cell types electrochemically interact with other cells, which may lead to the identification and characterization of the potential “seizure-causing” cell type in terms of physiology, morphology, connectivity and whole-genome gene expression profile. Seizures in TSC are often resistant to current anticonvulsant medications. While surgical removal of CT has been established as an effective treatment for some of TSC patients, these procedures carry the risk of invasive surgery and access is often limited due to various socioeconomic and medical concerns. Developing novel, alternative therapeutic interventions for pharmacoresistant seizures and cognitive comorbidities associated with TSC is thus a very pressing issue. This preclinical research using human TSC tissue, despite being short-term and exploratory, may provide a critical steppingstone closer to identify new targets for developing not only novel drugs to stop seizures, but also novel agents targeting the underlying mechanisms to cure seizures. The detailed knowledge derived from human TSC tissue can be both reverse and forward translated, bridging the gap between benchside basic and bedside clinical TSC studies. This is particularly relevant for TSC since TSC mouse models cannot fully recapitulate the TSC. The outcome of this research has the potential for unusual impact on clinical TSC research and patient care. First, if the critical components in human tissue for seizure generation (abnormal cell types and connection) can be identified and confirmed, forward translational studies could be prompted with TSC patients to develop the biomarkers for diagnosis and treatment, as well as the prognosis of diseases. Identifying specific makers for “seizure-causing” cell types based on their whole-genome transcriptional dataset could be the first step in this direction. Identification of reliable biomarkers could g
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910079
Entities
People
- Xiaolong Jiang
Organizations
- Baylor College of Medicine
- United States Army