Landscape of spatial disruption of homeostasis in the middle temporal gyrus of epileptic patients.

Epilepsy, a prevalent neurological disorder, significantly impacts cognitive function and quality of life, yet its underlying mechanisms remain incompletely understood. This study investigates the middle temporal gyrus (MTG) in epileptic patients using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to elucidate cellular and spatial disruptions associated with epilepsy. We identified distinct cellular clusters and layer-specific gene expression patterns that were significantly altered in epileptic patients compared to controls. Notably, L5_6-related neurons increased, and L2_4-related neurons decreased in epilepsy, highlighting a reorganization of neuronal networks. Spatial mapping revealed significant alterations in the spatial domains of key marker genes, including NPY and GFAP, particularly in L5_6 layers. Using the spatial transition tensor (STT) algorithm, we characterized the spatial dynamics and multistability of neuronal populations, identifying regions of spatial stability and instability. NPY and GFAP emerged as critical genes linked to spatial homeostasis disruption. Additionally, specific L5_6 cell subtypes, such as those expressing TMSB10 and RPS23, exhibited significant spatial homeostasis disruption in epilepsy. These findings underscore the importance of integrating single-cell and spatial transcriptomic data to map cellular and spatial changes at high resolution, providing a comprehensive understanding of the interactions between cell types and their microenvironments. This study enhances our understanding of the molecular and cellular underpinnings of epilepsy and identifies potential therapeutic targets for restoring spatial stability and neuronal function in the epileptic brain.