Multi-modal characterization and simulation of human epileptic circuitry

Temporal lobe epilepsy is the fourth most common neurological disorder, with about 40% of patients not responding to pharmacological treatment. Increased cellular loss is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions, the impact of the disease at the cellular level remains unclear. Here, we show that hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from patients with epilepsy. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume and spine density. Single-nucleus RNA sequencing combined with simulations ascribes the changes to three conductances: BK, Cav2.2, and Kir2.1. In a network model, we show that these changes related to disease progression bring the circuit into a more excitable state, while reversing them produces a less excitable, “early-disease-like” state. [Display omitted] •Transcriptomics in human granule cells separate early vs. late disease state•Phenotypic changes in human granule cells occur across modalities•Changes in granule cell excitability are linked to three ionic conductances The cellular changes brought about by temporal lobe epilepsy in humans remain unknown. Buchin et al. generate a multimodal dataset from human hippocampal surgical tissue to map cellular changes linked to disease progression. They find three ion conductances that explain changes across modalities.