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 re-sponding 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 inter-ventions, 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-likestate.

Automated summary

Temporal lobe epilepsy, a common neurological disorder, often does not respond to pharmacological treatment. This study found that hippocampal granule cells undergo changes, becoming more excitable and increasing in size, as the disease progresses. The changes in cellular properties are linked to specific conductances. A network model demonstrated that these changes lead to an increase in circuit excitability, and reverting them can restore a less excitable early-disease state.