A UNIFYING NEUROPATHOLOGICAL SPECTRUM UNDERLIES MEDIAL TEMPORAL LOBE EPILEPSY

Medial temporal lobe epilepsy (mTLE), characterized by seizures arising from the hippocampus, is the most common form of focal epilepsy, with up to 70% of patients failing to respond to medication. Regional patterns of neuronal loss in the hippocampus have been used to classify mTLE into discrete histopathological subtypes. Here, using single-cell spatial transcriptomics, we examine molecular-cellular alterations in mTLE and reassess this discrete-subtype framework.
We collected single-cell spatial transcriptomic data (Xenium, 10x Genomics) from the hippocampus of 18 individuals, including epilepsy samples with varying degrees of hippocampal sclerosis, and postmortem non-epileptic controls, using a 366-gene panel. Our gene panel included marker genes for major hippocampal cell types, such as excitatory and inhibitory neurons and multiple glial populations, as well as genes reported to be affected in epilepsy.
Our data reveal previously unresolved signatures of molecular-cellular vulnerability in mTLE, including neuronal degeneration, glial remodeling, and region-specific susceptibility across individuals. At the level of molecules, cells, and regions, we identify a singular pathological spectrum across histopathological subtypes. This unified axis captures major patterns of molecular variation in mTLE and highlights conserved cellular programs with therapeutic relevance. Finally, our dataset provides a valuable resource for the epilepsy and hippocampal research communities, enabling a deeper understanding of human hippocampal organization and dysregulation in mTLE.