Deciphering brain mosaicism in drug-resistant epilepsy at cellular resolution

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Project Summary This administrative supplement will provide a predoctoral research training and mentorship program for Ms. Sydney Townsend under the parent project R01NS129784 entitled “Deciphering brain mosaicism in drug- resistant epilepsy at cellular resolution.” Ms. Townsend’s goal is to study the long-term consequences of pediatric drug-resistant epilepsy, while developing her own analytical skills with a focus on single-cell transcriptomic and epigenomic data. Early-life seizures, particularly those that are difficult to control with medication, have profound consequences for brain development and function later in life. Up to half of children with epilepsy exhibit intellectual disability and long-term deficits in communication, cognition, and behavior. Therefore, it is a critical need to understand how early-life seizures alter brain development to develop treatment opportunities. Epilepsy has been linked to transcriptional and epigenetic remodeling in the adult brain, but a major barrier to understanding its developmental effects has been dissecting the acute vs. long-lasting contributions of individual cell types. Understanding both acute and long-lasting molecular responses to early-life epilepsy on a cellular level would inform the mechanisms through which long-term cognitive and behavioral deficits arise. This application aims to bridge this gap in knowledge by using cutting-edge single-cell multiomics techniques to investigate epigenetic and transcriptional changes in developing hippocampal cells following early-life seizures using a mouse model. The second aim will map long-lasting molecular changes to hippocampal-dependent behavioral consequences. The central hypothesis is that early-life seizures have long-lasting cell-type-specific effects on transcription and chromatin accessibility that may account for the long-term cognitive and behavioral effects. The rationale for this project is that understanding these changes will ultimately present new treatment opportunities. The research proposed in this supplement application is highly innovative because it takes a new approach to understanding the long-term sequalae of early-life seizures by leveraging leading-edge advances in single-cell multiomics. The research aligns with the aims of the parent project by examining molecular and functional effects of early-life epilepsy at cellular resolution, while addressing career training goals for Ms. Townsend and promoting diversity in scientific research.